CN102812022A - Thiazole and oxazole kinase inhibitors - Google Patents
Thiazole and oxazole kinase inhibitors Download PDFInfo
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- CN102812022A CN102812022A CN201180013642XA CN201180013642A CN102812022A CN 102812022 A CN102812022 A CN 102812022A CN 201180013642X A CN201180013642X A CN 201180013642XA CN 201180013642 A CN201180013642 A CN 201180013642A CN 102812022 A CN102812022 A CN 102812022A
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- pyridine
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- oxazoles
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- 0 CCC1CCN(*)CC1 Chemical compound CCC1CCN(*)CC1 0.000 description 6
- NWBGWMHETOKOKA-LOFVUVNCSA-N C/C=C/C=N\C(\Nc1cccc(-c2cnc(/C=C/c(cc3)ccc3OC)[o]2)n1)=C/C Chemical compound C/C=C/C=N\C(\Nc1cccc(-c2cnc(/C=C/c(cc3)ccc3OC)[o]2)n1)=C/C NWBGWMHETOKOKA-LOFVUVNCSA-N 0.000 description 1
- DPTCGFPTJLYOAC-UHFFFAOYSA-N Cc1cc(Nc2nc(-c3cnc(-c(cc4)cc5c4[nH]cc5)[o]3)c(C)cc2)ncc1 Chemical compound Cc1cc(Nc2nc(-c3cnc(-c(cc4)cc5c4[nH]cc5)[o]3)c(C)cc2)ncc1 DPTCGFPTJLYOAC-UHFFFAOYSA-N 0.000 description 1
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- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
- A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
- A61K31/444—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a six-membered ring with nitrogen as a ring heteroatom, e.g. amrinone
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- C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
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- C07D417/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing three or more hetero rings
Abstract
The present invention is concerned with substituted azole derivatives that selectively modulate, regulate, and/or inhibit signal transduction mediated by certain native and/or mutant proteine kinases implicated in a variety of human and animal diseases such as cell proliferative, metabolic, allergic, and degenerative disorders. In particular, several of these compounds are potent and selective Flt-3 inhibitors or/and syk inhibitors.
Description
Technical field
The present invention relates to replace oxazole derivatives; The protein kinase mediated signal transduction of and/or sudden change natural by some is adjusted, is regulated and/or suppress on said derivatives selectively ground, and said protein kinase is relevant with the disease (like cell proliferation illness, metabolic disorder, allergic conditions (allergic disorders) and degeneration illness) of multiple humans and animals.Especially, several in these compounds are strong selectivity Flt-3 suppressor factor and/or syk suppressor factor of imitating.
Background technology
Protein kinase is receptor type or non-receptor type albumen, and the terminal-phosphate of ATP is transferred to (like tyrosine residues, threonine residues, serine residue) on the proteic amino-acid residue, makes signal transduction pathway activation or inactivation thus.Known these albumen are participated in many cell mechanisms that under ruined situation, cause illness (like unusual cell proliferation and migration and inflammation).
Up to now, the known protein kinases has surpassed 500 kinds.Included at the interior well-known Abl that has; Akt1; Akt2; Akt3; ALK; Alk5; A-Raf; Axl; B-Raf; Brk; Btk; Cdk2; Cdk4; Cdk5; Cdk6; CHK1; C-Raf-1; Csk; EGFR; EphA1; EphA2; EphB2; EphB4; Erk2; Fak; Fes; Fer; FGFR1; FGFR2; FGFR3; FGFR4; Flt-3; Fms; Frk; Fyn; Gsk3 α; Gsk3 β; HCK; Her2/Erbb2; Her4/Erbb4; IGF1R; IKK β; Irak4; Itk; Jak1; Jak2; Jak3; Jnk1; Jnk2; Jnk3; KDR; Kit; Lck; Lyn; MAP2K1; MAP2K2; MAP4K4; MAPKAPK2; Met; Mer; MNK1; MLK1; MTOR; P38; PDGFR α; PDGFR β; PDPK1; PI3K α; PI3K β; PI3K δ; PI3K γ; Pim1; Pim2; Pim3; PKC α; PKC β; PKC θ; Plk1; Pyk2; Ret; ROCK1; ROCK2; RON; Src; Stk6; Syk; TEC; Tie2; TrkA; TrkB; Tyk2; VEGFR1/Flt-1; VEGFR2/Kdr; VEGFR3/Flt-4; Yes and Zap70.
In tyrosine kinase receptor, Flt-3 has caused special interest.In fact, the acute myelogenous leukemia of 60%-80% (AML) parent cell (blasts) is expressed the Flt-3 acceptor, and said Flt-3 acceptor is in the acceptor of Flt-3 part and the acute lymphoblastic leukemia (ALL) that is present in high per-cent.Part and acceptor are discerned (Hannum etc., Nature, 368, pp.643-648,1994 by Direct Recognition or at U119 by cooperation; Rosnet etc., Genomics, 9, pp.380-385,1991).Differentiation and the propagation of Flt-3 mediation normal hematopoiesis stem cell, and propagation in the mediation AML parent cell and existence signal.Though Flt-3 is the most common with the wild-type formal representation; But 30%-35% suffers from the patient's of AML white blood disease clone (Nakao etc., Leukemia, 12; Pp.1911-1918,1996) express the Flt-3 mutant that the internal series-connection that comprises nearly film domain encoding sequence repeats (Flt-3ITD).The autonomous growth that this sudden change causes the composition activation of acceptor and do not rely on cytokine.It is reported, contain sudden change (Flt-3D835) (Yamamoto etc., Blood, 97, pp.2434-2439,2001) near the Flt-3 activation ring of one group of AML patient (~ 7%) the Asp835 amino acid sites.According to another report, the Flt-3 sudden change is present among the Secondary cases AML with 15% frequency, and maybe be relevant with disease progression or the recurrence of AML.
Often prognosis is not good to have the patient of Flt-3 sudden change, and is accompanied by the remission time and the DFS rate (disease free survival) of reduction.For treatment hematopoietic disorder and malignant hematologic disease (hematological malignancies), the natural and/or kinase whose specific inhibitor of sudden change Flt-3 shows as attractive target.
Spleen tyrosine kinase (Syk) (intracellular protein Tyrosylprotein kinase) is key mediation body (the Wong Br etc. that comprise the immunity receptor signal in many inflammatory cells of B cell, mastocyte, scavenger cell and neutrophil leucocyte; (2004); Expert Opin Investig Drugs; 13,743-762).Syk also in non-hematopoietic cell appearance inoblast, breast cancer cell, colon cancer cell, liver cell, neuronal cell and vascular endothelial cell wide expression (Okamura S etc., (1999), Oncol Res, 11,281-285).Originally, Syk is considered to mainly signal at immunity receptor (like Fc acceptor (FcR) and B-cell receptor (BCR)) and sends in (signaling) and work.Yet; Recent research has demonstrated pivotal player (Yamada T etc., (2001), the J Immunol of Syk in the cell signal of various kinds of cell stimulator (it is plain to comprise that IL-1, tumor necrosis factor-alpha (TNF α), LPS and β 1-integrate) sends; 167,283-288).For example, Syk can be by TNF α activation, cause MAKP phosphorylation and NF-κ B transposition in the hematopoietic cell system (Takada Y and Aggarwal BB (2004), J Immunol, 173,1066-1077).Produce in the nasal polyp inoblast IL-1 inductive chemokine also through the Syk activation mediate (Yamada T etc., (2001), J Immunol, 167,283-288).Syk has become the potential treatment target spot that is used to treat allergic conditions and autoimmune disorder.
Summary of the invention
Goal of the invention
Therefore; Main purpose of the present invention is to find strong alternative cpd of imitating, and said compound can suppress the Flt-3 and/or the syk of the Tyrosylprotein kinase of the protein kinase of wild-type and/or sudden change, especially wild-type and/or sudden change, more particularly wild-type and/or sudden change.
Many different compounds are described as the Flt-3 tyrosine kinase inhibitor, for example, AG1295 and AG1296; Come appropriate for Buddhist nun (Cephalon); CEP-5214 and CEP-7055 (Cephalon); CHIR-258 (Chiron Corp.); EB-IO and IMC-EBlO (ImClone Systems Inc.); GTP-14564 (Merk Biosciences UK); Midostaurin (Novartis AG); MLN 608 (Millennium USA); MLN-518 and MLN-608 (Millennium Pharmaceuticals Inc.); SU-11248 (Pfizer USA); SU-11657 (Pfizer USA); SU-5416 and SU-5614; THRX-165724 (Theravance Inc.); AMI-10706 (Theravance Inc.); VX-528 and VX-680 (Novartis Switzerland, Merck&Co USA); And XL-999 (Exelixis USA); AC220 (Ambit Biosciences Corp.USA).Following PCT international application and U.S. Patent application disclose other kinase modulator, comprise the regulator of Flt-3: WO2002032861, WO 2002092599, WO 2003035009, WO 2003024931, WO 2003037347, WO 2003057690, WO 2003099771, WO2003024969, WO 2004005281, WO 2004016597, WO 2004018419, WO 2004039782, WO 2004043389, WO 2004046120, WO2004058749, WO 2004058749, WO 2008016665.
It is reported, and compound R 406 (Rigel Pharmaceuticals) inhibition Syk (Braselmann, Taylor etc., J Pharmacol Exp Ther, (2006), 319 (3), 998-1008).What is interesting is that behind Syk, R406 to have suppressed the autophosphorylation (Braselmann, Taylor etc., 2006) of Flt-3 the most by force with imitating than the active low about 5 times effectiveness of Syk.Although do not know Rigel suppressor factor R406 cutter system really, data presentation goes out, and it is useful clinically that the kinases that mediation survival signal in lymphocyte is sent suppresses.
Especially; The present invention aims to provide and is used for protein kinase, method and the compound that especially tyrosine kinase mediated signal transduction is optionally adjusted, regulated and/or suppresses natural by some and/or sudden change, and said protein kinase, especially said Tyrosylprotein kinase are relevant with the disease (like cell proliferation illness, metabolic disorder, allergic conditions and degeneration illness) of multiple humans and animals.Particularly, these compounds are strong selectivity Flt-3 and/or Syk suppressor factor of imitating.
The present invention particularly aims to provide the method for treatment AML or ALL.
Invention is described
In arrestin kinases, especially Tyrosylprotein kinase, the ability to of Flt-3 and/or Flt-3 two mutants (particularly Flt-3ITD) and/or Syk more particularly, The compounds of this invention is screened.
About the present invention, it is natural and/or the strong effect selective depressant of sudden change Flt-3 that the inventor has found to have in ， Zai oxazole and the thiazole derivative specific substituted compound.These compounds are the good candidate that are used to treat cell proliferation illness and/or Flt-3 associated conditions.This type of illness is unusual cell proliferation and migration and inflammation, and wherein Flt-3 expresses and should be suppressed, or need optionally adjust, regulates and/or suppress natural and/or sudden change Flt-3 Mediated Signal Transduction by some.Especially, the present invention relates to be used to treat the method and the compound of hematopoietic disorder and malignant hematologic disease.This type of illness comprises acute myelogenous leukemia and acute lymphoblastic white blood disease.
About the present invention, it is strong selectivity Syk suppressor factor of imitating that the inventor finds to have in ， Zai oxazole and the thiazole derivative specific substituted compound.
Embodiment
Therefore, the present invention relates to belong to the compound that replaces oxazole derivatives.These compounds can optionally suppress to relate to protein kinase, especially Tyrosylprotein kinase, the signal transduction of tyrosine kinase phosphorylation Flt-3 and mutant forms and/or syk more particularly.
In the description of preceding text, any mentioning of protein kinase, especially Tyrosylprotein kinase all impliedly related to Flt-3 and/or syk.In the first embodiment, the present invention is directed to the compound of formula I, but the free alkali form of the compound representative species of said formula I or its pharmacy acceptable salt:
Formula I
Wherein, substituent A, Q, X, the R among the formula I
1, R
2, R
3, V and W be as giving a definition:
A is one of following group:
I) N (R
4) (CH
2)
n, wherein, 0<n<3;
Ii) O (CH
2)
n, wherein, 0<n<3;
Iii) S (CH
2)
n, wherein, 0<n<3;
Iv) (CH
2)
n, wherein, 0≤n<4;
V) C (O) (CH
2)
n, wherein, 0<n<3;
vi）C(R
4)=C(R
5)；
vii）C≡C(R
5)；
R
4And R
5Be hydrogen, C independently of one another
1-4Alkyl, C
2-6Thiazolinyl, C
2-6Alkynyl, C
3-7Naphthenic base, C
1-4Haloalkyl, C
1-4Alkoxyl group, C
1-4Hydroxyalkyl, C
1-4Alkylamino;
X is CH or N;
V is O or S;
Q is selected from:
I) alkyl
1Group, or
Ii) aryl
1Group, or
Iii) heteroaryl
1Group;
With alkyl
1Group definition is straight chain, side chain or the group of naphthene base that comprises 1-10 carbon atom, and optional replaces with following radicals: one or more heteroatomss, like halogen (being selected from F, Cl, Br or I), oxygen and nitrogen; And trifluoromethyl, carboxyl, cyanic acid, nitro, formyl radical; And CO-R, COO-R, CONR-R ', SO
2-R and SO
2NR-R ', wherein, R and R ' they are the straight or branched alkyl group that comprises 1-10 carbon atom, and optional with at least one heteroatoms, particularly halogen (being selected from F, Cl, Br or I), oxygen and nitrogen replacement; And naphthenic base or aryl
1Group or heteroaryl
1Group;
With aryl
1Group definition be phenyl or the ring arbitrary position on have one or more substituent arbitrary combination the substituted-phenyl variant, said substituting group for example:
-halogen (being selected from I, F, Cl or Br);
-alkyl
1Group;
-group of naphthene base, aromatic yl group or heteroaryl groups;
-trifluoromethyl, O-alkyl, carboxyl, cyanic acid, nitro, formyl radical, hydroxyl, NH-alkyl, N (alkyl) (alkyl) and amino group;
-NRCO-R ' or NRCOO-R ' or NRCONR '-R " or NRSO
2-R ' or NRSO
2NR '-R " or CO-R or COO-R or CONR-R ' or SO
2-R or SO
2NRR ', wherein, R, R ' and R " are selected from hydrogen, alkyl, aryl or heteroaryl groups independently of one another;
With heteroaryl
1Group definition be for can having the pyridyl, pyrimidyl, pyrazinyl, pyridazinyl, thienyl, thiazolyl, imidazolyl, pyrazolyl, pyrryl, furyl 、 oxazolyl 、 isoxazolyl, triazolyl, tetrazyl, indyl, benzoglyoxaline, benzoxazole, benzothiazole, quinolyl group etc. of one or more substituent arbitrary combination in addition on arbitrary position of ring, said substituting group for example:
-halogen (being selected from F, Cl, Br or I);
-alkyl
1Group;
-naphthenic base, aryl or heteroaryl groups;
-trifluoromethyl, O-alkyl, carboxyl, cyanic acid, nitro, formyl radical, hydroxyl, NH-alkyl, N (alkyl) (alkyl) and amino group;
-NRCO-R ' or NRCOO-R ' or NRCONR '-R " or NRSO
2-R ' or NRSO
2NR '-R " or CO-R or COO-R or CONR-R ' or SO
2-R or SO
2NRR ', wherein, R, R ' and R " are selected from hydrogen, alkyl, aryl or heteroaryl groups independently of one another;
R
1, R
2And R
3Be selected from hydrogen, halogen (being selected from F, Cl, Br or I) independently of one another, comprise the straight or branched alkyl of 1-10 carbon atom; Said straight or branched alkyl is optional to be replaced with following group: one or more heteroatomss, like halogen (being selected from F, Cl, Br or I), oxygen and nitrogen; And trifluoromethyl, C
1-6Alkoxyl group, amino, C
1-6Alkylamino, two (C
1-6Alkyl) amino, carboxyl, cyanic acid, nitro, formyl radical, hydroxyl, CO-R, COO-R, CONR-R ', SO
2-R and SO
2NR-R ', wherein, R and R ' are selected from hydrogen, alkyl, aryl or heteroaryl groups independently of one another;
W is an aryl
1Or heteroaryl
1Aryl
1And heteroaryl
1The as indicated above definition.
Except as otherwise noted (for example, through the mark alkyl
1, aryl
1Or heteroaryl
1), for the purposes of the present invention, term " alkyl group " mean any straight or branched, replacement or unsubstituted C
1-C
10Alkyl group is like C
1-C
4Or C
1-C
6Alkyl group, especially methyl, ethyl group, propyl group, preferable methyl.Term " group of naphthene base " means saturated or part is undersaturated, comprise shown in monocycle, condensed-bicyclic or the bridging of annular atoms number encircle aggregate (assembly) more.This comprises and replacing or unsubstituted group of naphthene base.For example, group of naphthene base can be C
3-C
10Alkyl group is like C
5Or C
6Alkyl group, especially cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, suberyl or ring octyl group group etc.Group of naphthene base comprises the heterocycle that obtains through the one or more carbon atoms with one or more nitrogen, oxygen or sulphur atom substituted cycloalkyl group.Comprise the ring as mentioned below alkyl water solubilizing group (cycloheteroalkyl water-solubilizing groups) of mixing.The term that this paper was used alone or in combination " alkoxy base " comprises the alkyl group that is connected to the oxygen linker atom.The instance of suitable alkoxy base comprises methoxyl group, oxyethyl group, positive propoxy, isopropoxy, n-butoxy, sec.-butoxy, tert.-butoxy.Term " aromatic yl group " means and replaces or unsubstituted, as to comprise 6-10 ring carbon atom monocycle or condensed-bicyclic shape aromatic nucleus aggregate.For example, aryl can be phenyl or naphthyl, preferred phenyl.Term " heteroaryl groups " is one or more for heteroatomic aromatic yl group as defined above in the ring members.For example; Heteroaryl groups comprises that pyridyl, indyl, indazolyl 、 quinoxalinyl, quinolyl, benzofuryl, benzopyranyl, benzimidazole thiophanate are for pyranyl, benzo [1,3] dioxole, imidazolyl, benzimidazolyl-, pyrimidyl, furyl 、 oxazolyl 、 isoxazolyl, triazolyl, tetrazyl, pyrazolyl, thienyl etc.
In some embodiments, Q and W part are substituted aromatic yl group or heteroaryl groups independently of one another, and wherein, at least one in the substituting group is the water solubilizing group.Term as used herein " water solubilising " group is the group with water-wet behavior, and this water-wet behavior is enough to improve or increase water-soluble (the comparing with the similar compound that does not comprise this group) of the compound that comprises this group.Can realize said water-wet behavior through any way, for example through being included in functional group's (for example, carboxylic acid, sulfonic acid, phosphoric acid, amine etc.) of ionization formation alive part under the working conditions; The group (for example, quaternary ammonium group) that comprises permanent charge; And/or heteroatoms or heteroatom group (for example, O, S, N, NH, N-(CH
2)
zR, N-(CH
2)
z-C (O) R, N-(CH
2)
z-C (O) OR, N-(CH
2)
z-S (O)
2R, N-(CH
2)
z-S (O)
2OR, N-(CH
2)
z-C (O) NRR ' etc.; Wherein, z is the integer of 0-6, and R and R ' are selected from hydrogen independently of one another, comprise the straight or branched alkyl of 1-10 carbon atom; Said straight or branched alkyl is optional to be replaced with following group: one or more heteroatomss, like halogen (being selected from F, Cl, Br and I), oxygen and nitrogen; And C
1-6Alkoxyl group, C
1-6Alkylamino, C
1-6Alkyl hydroxy, two (C
1-6Alkyl) amino; And aryl and heteroaryl groups.
In some embodiments, said water solubilizing group is optional 1-5 the assorted alkyl of substituent ring that comprise, and said substituting group itself can be the water solubilizing group.
In specific embodiment, said water solubilizing group is a following formula:
Wherein, L is selected from the group of being made up of CH and N, M be selected from the group of forming by following group :-CH (R)-,-CH
2-,-O-,-S-,-NH-,-N ((CH
2)
z-R)-,-N ((CH
2)
z-CO) R)-,-N ((CH
2)
z-C (O) OR)-,-N ((CH
2)
z-S (O)
2R)-,-N ((CH
2)
z-S (O)
2OR)-with-N ((CH
2)
z-C (O) NRR ')-; Wherein, Z is the integer of 0-6; R and R ' are selected from hydrogen independently of one another, comprise the straight or branched alkyl group of 1-10 carbon atom, and said straight or branched alkyl group is optional to be replaced with following group: one or more heteroatomss, like halogen (being selected from F, Cl, Br or I), oxygen and nitrogen; And C
1-6Alkoxyl group, C
1-6Alkylamino, C
1-6Alkyl hydroxy, two (C
1-6Alkyl) amino; And aryl and heteroaryl groups; But L and M can not be respectively CH and CH simultaneously
2
In another specific implementations, said water solubilizing group is selected from the group of being made up of following group: morpholino, piperidyl, (C
1-C
6) N-Alkylpiperidine base, N-methyl piperidine base, N-(4-piperidyl) piperidyl, 4-(l-piperidyl) piperidyl, 1-pyrrolidyl piperidyl, 4-morpholino piperidyl, 4-(N-methyl-l-piperazinyl) piperidyl, piperazinyl, (C
1-C
6) N-alkylpiperazine base, N methyl piperazine base, N-ethylpiperidine base, N-ethyl piperazidine base, N-naphthenic base piperazinyl, N-cyclohexyl piperazinyl, pyrrolidyl, N-alkyl pyrrolidine base, N-methylpyrrole alkyl, diaza
Base (diazepinyl), N-N-ethyl pyrrole N-alkyl, N-alkyl azepine
Base (N-alkyl azepinyl), N-methyl azepine
Base, N-ethyl azepine
Basic, high piperazinyl, the high piperazinyl of N-methyl, the high piperazinyl of N-ethyl and imidazolyl etc.
The arbitrary combination of related kind contained in term " one or more ".
The preferred compound of the present invention is the compound of formula Ia:
Formula Ia
Wherein, A, Q, R
1, R
2, R
3Define with V such as preceding text, and W
1Be selected from hydrogen, halogen (being selected from F, Cl, Br or I), comprise one or more in the straight or branched alkyl group of 1-10 carbon atom; Said straight or branched alkyl group is optional to be replaced with following group: one or more heteroatomss, like halogen (being selected from F, Cl, Br or I), oxygen and nitrogen; And trifluoromethyl, C
1-6Alkoxyl group, amino, C
1-6Alkylamino, two (C
1-6Alkyl) amino, carboxyl, cyanic acid, nitro, formyl radical, hydroxyl, CO-R, COO-R, CONR-R ', SO
2-R and SO
2NR-R ', wherein, R and R ' are selected from hydrogen, alkyl, aryl or heteroaryl groups independently of one another.
In specific embodiment, V is O.In another specific embodiment, V is S.
In one embodiment, R
1, R
2, R
3Be Wasserstoffatoms.
In formula I and formula Ia, A is preferably selected from CH
2-CH
2, S, S-CH
2, NH-CH
2, CH=CH, C ≡ C or do not exist.
An embodiment according to formula I and formula Ia; Q is aryl or heteroaryl groups, and is optional by following group replacement: the alkoxy base of halogen (being selected from F, Cl, Br or I), cyanic acid, trifluoromethyl, amino, as above definition, the alkyl group or the nitro of as above definition.
According to the embodiment of formula I and formula Ia, Q is a naphthenic base, the naphthenic base that for example as above defines, and be preferably selected from cyclohexyl, cyclopentyl, suberyl and ring octyl group.
In one embodiment, W
1Be hydrogen, methyl, ethyl, propyl group, sec.-propyl, butyl, isobutyl-, sec.-butyl, the tertiary butyl, methoxyl group, oxyethyl group or propoxy-, said W
1Optional have one or more substituting groups, and said substituting group is nitrogen, oxygen or halogen (being selected from F, Cl, Br or I), for example trifluoromethyl or trifluoromethoxy, hydroxyl, alkylamine and hydroxyalkyl for example.
In specific formula I compound, the present invention is directed to compound with following formula:
Formula II
Wherein, R
1, R
2, R
3, X, V and W have implication mentioned above; And
Wherein, R
6, R
7, R
8, R
9And R
10Be selected from hydrogen, halogen (being selected from F, Cl, Br or I) independently of one another, comprise the straight or branched alkyl group of 1-10 carbon atom; Said straight or branched alkyl group is optional to be replaced with following group: one or more heteroatomss, like halogen (being selected from F, Cl, Br or I), oxygen and nitrogen; And trifluoromethyl, C
1-6Alkoxyl group, amino, C
1-6Alkylamino, two (C
1-6Alkyl) amino, carboxyl, cyanic acid, nitro, formyl radical, hydroxyl, CO-R, COO-R, CONR-R ', SO
2-R and SO
2NR-R ', wherein, R and R ' are selected from hydrogen, alkyl, aryl or heteroaryl groups independently of one another.
According to the present invention, the compound of formula II can be the compound of the formula Ia mentioned above that comprises each embodiment, and wherein, A-Q is following:
This compounds can be represented by Formula Il a:
Formula IIa
Wherein, R
1, R
2, R
3, R
6, R
7, R
8, R
9And R
10, V and W1 have implication mentioned above.
In specific formula I compound, the present invention is directed to compound with following formula:
Formula III
Wherein, Z is an aryl
1Or heteroaryl
1R
1, R
2, R
3, X, V, W, aryl
1And heteroaryl
1Has implication mentioned above.
According to the present invention, the compound of formula III can be the compound of the defined formula Ia of preceding text that comprises each embodiment, and wherein, A-Q is the Z like the preceding text definition.
This compounds can be represented by Formula Il Ia:
Formula III a
Wherein, R
1, R
2, R
3, V, W1 and Z have implication mentioned above.
Can use following general experimental program to prepare The compounds of this invention:
The method of (Tetrahedron Lett., 1972,23,2369) such as utilization Van Leusen makes the aromatic aldehyde and tolysulfonyl ylmethyl isonitrile (TosMIC) reaction of general formula (2), prepares corresponding 5-aryl substituted oxazole (3).With organometallic reagent and DMF, use literature method to introduce the aldehyde (Org.Lett., 2004,6,1887) that aldehyde radical prepares noncommodityization by corresponding bromination aromatic compound (1).
Then; Under situation about being necessary; Use known palladium-catalyzing N-arylation experimental program, usefulness is suitable for the part of each substrate and the combination of mineral alkali makes general formula (3) compound that has instead atom (for example Br) further functionalized, thus the analogue (4) that provides N-to connect.Through suitable organic bases Shi oxazole part deprotonation, carry out close electric chlorination or iodate subsequently, above-mentioned steps is used to prepare 2-Lv oxazole or 2-Dian oxazole compound (5).This makes and can obtain various molecule family through by amine or mercaptan nucleophilic reagent chlorine being replaced, thereby generates the compound of general formula (6).Similarly; Use classical palladium catalyzed coupling reaction (Diederich, F. and Stang P.J., " Metal-catalyzed Cross-coupling Reactions "; WILEY-VCH; 1998), chlorination or iodate De oxazole (5) are used to prepare the further substituted analogue of C-2 (7), Stille that the palladium catalyzed coupling reaction of said classics for example carries out respectively or Suzuki coupling (diagram 1) under the situation of stannane (stannane) or aryl boric acid existence.The method of (Org.Lett., 2009,11,4156) such as use Matsuyama is used to prepare further analogue (14) through the catalytic alkynylization of nickel with compound (4).
Diagram 1
In addition, also Wei substituted oxazole (4) is used for the catalytic C-H priming reaction of palladium (diagram 2), thereby according to (Synthesis, 2009,20,3511 such as Besselievre; Org.Lett., method regioselectivity ground 2008,10 (18), 4029) is installed in aromatic nucleus on the C-2 position.In addition,, Zhe Xie oxazole midbody (4) and a large amount of β-bromstyrols are reacted, prepare corresponding 2-Ben Yi Xi Ji oxazole (8) through similar method.Use the Hunsdieker method of having delivered to prepare the employed noncommodity bromstyrol of this paper by corresponding cinnamic acid; Or, carry out debrominate with triphenylphosphine through the Hirau reduction subsequently through the effect of Corey-Fuchs dibrominated, prepare the employed noncommodity bromstyrol of this paper by corresponding aldehyde.Perhaps, can come Zhi Bei oxazole (8) by halo analogue (5) through carrying out the catalytic cross-coupling of palladium with suitable boric acid or ester.As at Hudlicky; " Reductions in Organic Chemistry ", John Wiley and Sons is described in 1984; Through reducing, prepare other suppressor factor family (9) by two keys of normal pressure catalytic hydrogenation to Ben Yi Xi Ji oxazole (8).
Diagram 2
The thiazole for preparing general formula (13) through following method: use known Suzuki method (J.Med.Chem. respectively; 2005,48,224) or Negishi method (Tet.Lett.; 2010; 51,357-359) commercial 2-bromo thiazole and fragrant boric acid or organic zinc reagent are reacted, thereby obtain thiazole (10).Make the deprotonation of thiazole part through suitable organic bases, prepare compound (11) through close electric stannaneization (stannylation) subsequently.Next use 2, the 6-dibromo pyridine carries out the Stille linked reaction, obtains the pyridine bromide of formula (12).Classical palladium catalyzing N-arylation experimental program provides N-to connect analogue (13).Also can directly obtain analogue (13) (diagram 3) by compound (11) through the Stille coupling.
Diagram 3
In addition, by 2-[1,3] dioxolane-2-base-5-tributyl stannyl-thiazole XIV Synthetic 2-styryl thiazole (18) (J.Med.Chem., 2007,50,630) (diagram 4).Obtain the verivate of formula (16) with the mode that is similar to the rapid order of the described palladium catalyse two-step of preparation compound (13).Then; Make dioxolane (16) deprotection under acidic conditions; Use benzyl base triphenyl phosphonium salt and suitable alkali to pass through the classical Wittig reaction of corresponding aldehyde (17) subsequently, after isomer being separated, E-styryl thiazole family (18) is provided with classical chromatographic process.
Diagram 4
In formula I compound synthetic, R
1Schematically show with R and to be selected from R
1, R
2And R
3In one or more groups; X is a halogen; R
3Expression is selected from R
6, R
7, R
8, R
9And R
10In one or more groups.YR
2Expression amine groups or thiol group.Ar and Ar
1Expression aryl or heteroaryl groups.Hal representes halogen atom.
The invention further relates to the compound that is selected from following compound:
(4-methyl-pyridine-2-yl)-(6-oxazole-5-base-pyridine-2-yl)-amine;
[6-(2-chlorine-oxazoles-5-yl)-pyridine-2-yl]-(4-methyl-pyridine-2-yl)-amine;
[6-(2-iodine-oxazoles-5-yl)-pyridine-2-yl]-(4-methyl-pyridine-2-yl)-amine;
2-bromo-6-(2-pyridin-3-yl-thiazole-5-yl)-pyridine;
2-bromo-6-(2-[1,3] dioxolane-2-base-thiazole-5-yl)-pyridine;
[6-(2-[1,3] dioxolane-2-base-thiazole-5-yl)-pyridine-2-yl]-(4-methyl-pyridine-2-yl)-amine;
5-[6-(4-methyl-pyridine-2-base is amino)-pyridine-2-yl]-thiazole-2-formaldehyde.
These compounds are the good midbodys that are used for synthetic active compound of the present invention.
In second embodiment, the present invention relates to comprise the pharmaceutical composition of above-claimed cpd.
Therefore, the present invention relates to comprise the pharmaceutical composition of at least a The compounds of this invention and acceptable pharmaceutical excipient.
As is known to the person skilled in the art; Can use the various forms of vehicle that are adapted to the pattern that gives; The validity of some the promoted bioactive molecule in these forms is for example through promoting release performance (release profile) to make this bioactive molecule more effective for desired treatment on the whole.
Therefore; But pharmaceutical composition of the present invention can give with various forms, concrete example such as injectable forms, pulverizable form or form for ingestion, for example through intramuscular approach, intravenous route, subcutaneous route, intradermal routes, oral route, topical, rectum approach, vaginal approach, eye approach, nose approach, through skin approach or parenteral approach.The present invention has covered the purposes of The compounds of this invention aspect manufacturing compsn, especially pharmaceutical composition especially.
With proper dosage, use pharmaceutically acceptable carrier well known in the art, can this type of medicine be mixed with the pharmaceutical composition for oral administration form that is suitable for.Examples of such carriers makes pharmaceutical composition can be mixed with following preparation to be used for patient picked-up: tablet, pill, sugar-coat agent (dragees), capsule, liquid agent, gelifying agent, syrup, paste (slurries) and suspension liquor etc.Except that activeconstituents, these pharmaceutical compositions also can contain suitable pharmaceutically acceptable carrier (comprising vehicle and auxiliary agent), and said carrier helps active compound is processed into can be at the preparation that pharmaceutically uses.In the Remington ' of latest edition s Pharmaceutical Sciences, can find the preparation and give the technology further details (Maack Publishing Co., Easton, Pa.).
Compsn of the present invention also can take to be used for the form of the pharmaceutical composition or the make-up composition of topical administration.
This based composition form as follows appears: gelifying agent; Paste; Ointment (ointment); Creme; Emulsion agent; Liquid aqueous suspension liquor; Water-alcohol solution or oily solution; The perhaps dispersion agent of serum type or emulsion agent; Perhaps anhydrous gel agent or lipophilic gelifying agent; Otherwise perhaps through fat is dispensed into mutually aqueous phase or obtain, the liquid state of milk type (milk type) or the emulsion of semi solid consistency; Emulsion perhaps creme or gel-type, soft semi-solid denseness or suspension liquor; Perhaps alternatively, to vesica dispersion agent (vesicular dispersions), fine granule, microcapsule or the microemulsion of ionic and/or non-ionic type.According to these compsns of standard method preparation.
Compsn of the present invention comprises any composition that is generally used in dermatology and the makeup.Said composition can comprise and is selected from least a in the following composition: hydrophilic gelling agent or lipophilic jelling agent, hydrophilic acvator or lipophilic acvator, sanitas, tenderizer, viscosity strengthen polymkeric substance, wetting Agent for Printing Inks, tensio-active agent, sanitas, inhibitor, solvent and filler, inhibitor, solvent, spices, filler, sequestering agent, sterilant, deodorant agent and tinting material.
Oil as can be used among the present invention can be mentioned: MO (whiteruss), vegetables oil (liquid portion of shea butter, Trisun Oil R 80), animal oil, synthetic oil, silicone oil (cyclomethicone) and fluorinated oil.Also can be with Fatty Alcohol(C12-C14 and C12-C18), lipid acid (Triple Pressed Stearic Acid) and wax (paraffin, palm wax (carnauba), beeswax) as lipid material.
As can be used for emulsifying agent of the present invention, stearin, Polysorbate 60 and PEG-6/PEG-32/ glycol stearate mixture are at the row of consideration.
As hydrophilic gelling agent, can mention carboxy vinyl polymer (carbomer), PEMULEN TR2 (like propenoate/alkyl acrylate copolymer), SEPIGEL 305, polysaccharide (like hydroxypropylcellulose), clay and natural gum; As the lipophilic jelling agent, can mention metal-salt (like StAl) and hydrophobic silica or the TKK 021 and the Vilaterm of modified clay (like organic bentonite), lipid acid.
Can use as hydrophilic acvator: albumen or proteolysate, amino acid, polyvalent alcohol, urea, wallantoin, sugar and sugar derivatives, VITAMINs, starch and plant milk extract (the particularly extract of aloe (Aloe vera)).
Can use as the lipophilic acvator: Vogan-Neu (vitamin A) and verivate thereof, Viteolin (vitamin E) and verivate, indispensable fatty acid, ceramide and essential oil (essential oil).These reagent have increased extra preserving moisture or the characteristic of softening skin in use.
In addition, can comprise tensio-active agent in the compsn, so that darker penetrating (penetration) is provided to the compound (like tyrosine kinase inhibitor) that can remove mastocyte.
In the composition of being considered, the present invention includes: penetration enhancer is selected from the group of for example being made up of MO, water, ethanol, triactin, glycerine and Ucar 35; Flocculation agent (cohesion agent) is selected from the group of for example being made up of polyisobutene, Yodo Sol VC 400 and Z 150PH; And thickening material.
The chemical process that strengthens the medicine local absorption is well known in the art.For example, the compound that has the enhanced characteristic of penetrating comprises sodium lauryl sulphate (Dugard, P.H. and Sheuplein, R.J., " Effects of Ionic Surfactants on the Permeability of Human Epidermis:An Electrometric Study "; J.Ivest.Dermatol., V.60, pp.263-69,1973), dodecyl amine oxide (Johnson etc.; US 4,411,893), azone (Rajadhyaksha, US 4; 405,616 and 3,989,816) and Decylmethyl Sulphoxide (Sekura; D.L. and Scala, J., " The Percutaneous Absorption of Alkylmethyl Sulfides ", Pharmacology of the Skin; Advances In Biolocy of Skin, (Appleton-Century Craft) V.12, pp.257-69,1972).Observe, the polarity that improves head group in the amphipathic molecule makes it penetrate enhanced characteristic to be increased, but will be cost (Cooper, E.R. and Berner to increase its skin irritation characteristic; B., " Interaction of Surfactants with Epidermal Tissues:Physiochemical Aspects ", Surfactant Science Series, V.16; Reiger, M.M. writes, (Marcel Dekker; Inc.), pp.195-210,1987).
Second type of chemical intensifier is commonly referred to cosolvent.These materials are easy to carry out local absorption through various mechanism relatively, realize that for some medicines infiltration strengthens.Make the absorption of all cpds be able to the enhanced ability to demonstrating, (699 with Campbell etc. for Gale etc., U.S. Patent number 4,615 for ethanol; U.S. Patent number 4,460,372 and 4,379,454), (US 3 for methyl-sulphoxide; 740,420 with US 3,743,727 and US 4; 575,515) and glycerol derivative (US 4,322,433) be several instances of this compounds.
Pharmaceutical composition of the present invention also can be intended to be used for giving to the target area in patient respiratory road with aerosol formulations.
At US 5,906, disclose in 202 and be used for the apparatus and method that delivering drugs preparation aerosol sprays (aerosolized bursts).Preparation is preferably solution, for example the aqueous solution, acetic acid soln, water/acetic acid soln, salt brine solution, colloidal suspension liquid and crystallite suspension-s.For example, aerosol particles comprises activeconstituents mentioned above and carrier (for example, pharmaceutically active respiratory medications and carrier), and said aerosol particles forms through nozzle through promoting preparation, and said nozzle is preferably the form of flexible porous-film.Said particle has enough little size, makes still in air, to suspend the sufficiently long time when particle forms, thereby the patient can be sucked particle in patient's the lung.
The present invention has been contained at US 5,556, the system of describing in 611:
-be in liquid gas system in the pressurized vessel (with liquefied gas as propulsive gases (for example, lower boiling FCHC or propane, butane);
-suspension aerosols (active material particle is suspended in the liquid propelling mutually with solid-state form);
The gas system of-pressurization (using pressurized gas) like nitrogen, carbonic acid gas, nitrous oxide, air.
Therefore,, process pharmaceutical prepn: active substance is dissolved in or is dispersed in the suitable nontoxic medium, and said solution or dispersion liquid are atomized into aerosol, that is, extremely fine be distributed in the carrier gas through following steps according to according to the invention.This is feasible technically, for example is following form: aerosol propulsive gases bag; The pumping aerosol; Or itself become known for other device of liquid mist formation and solid atomizing, especially allow the device of accurate individual consumption.
Therefore, the present invention preferably has the administration valve of metering also to the aerosol device that comprises as above defined compound and this type of preparation.
Pharmaceutical composition of the present invention also can be intended to be used for giving in the nose.
About this point, those of ordinary skills will easily understand the pharmaceutically acceptable carrier that is used for giving to the nasal mucosa surface compound.At Remington ' s Pharmaceutical Sciences, the 16th edition, 1980, during Arthur Osol writes these carriers have been described, incorporate its disclosure into this paper by reference.
The selection of suitable carrier is depended on the specific type of being considered that gives.In order to give through the upper respiratory tract, can said compsn be mixed with solution, for example, buffering or non-cushioned water or isotonic saline solution; Or be mixed with suspension-s, be used for giving in the nose with drops or sprays.Preferably, this type of solution or suspension-s are isoosmotic for nose secretory product and have identical pH, about pH7.4 of for example about pH4.0-or pH6.0-pH7.0.Damping fluid should be a physical compatibility, takes a single example to comprise phosphate buffered saline buffer.For example, representational nasal decongestant is described as being buffered to pH about 6.2 (Remington ' s, the same, the 1445th page).Certainly, for nose and/or the upper respiratory tract gave, those of ordinary skills can easily confirm pH and the brine content that harmless aqueous carrier is suitable.
Also can carrier (comprising nose gelifying agent, creme, paste or ointment) in viscosity about 3000cps of for example about 10-or the common nose more than about 2500-6500cps be used to provide and surperficial the contacting more lastingly of nasal mucosa.Only by way of example, examples of such carriers viscosity preparation can be based on alkylcellulose well known in the art and/or other full-bodied physiologically acceptable carrier (referring to for example, the Remington ' s that preceding text are quoted).Preferred alkylcellulose for example, concentration is the methylcellulose gum more than the about 1000mg of the about 5mg-of every 100ml carrier.Only by way of example, preferred methylcellulose gum concentration is the about mg of the about 25mg-of every 100ml carrier.
Also can comprise other composition provides extra viscosity, moisture retention and desirable quality and smell to preparation, the MO of said other composition sanitas for example known in the art, tinting material, lubricated or viscosity or vegetables oil, spices, natural or synthetic plant milk extract (for example perfume oil) and wetting Agent for Printing Inks and viscosity intensifier (for example glycerine).Nose for solution of the present invention or suspension-s gives, and this area capable of using is used to generate the various devices of drop (drops), droplet (droplets) and spraying (sprays).
Another object of the present invention is; The dose dispenser of analytical unit in advance that will contain drip-feeding (dropper) or spraying plant is processed the medicine to be given that comprises one or more dosage, and said drip-feeding or spraying plant contain as drop or solution or the suspension-s sent as spraying.The present invention also comprises preparation through adding the test kit that suitable quantity of water is processed solution or suspension-s, and said test kit contains compound and any required salt and/or buffer reagent, sanitas and the tinting material etc. of one or more units dehydration dosage.
The present invention is directed against the purposes of said compound aspect the manufacturing medicine on the other hand.In other words; The present invention includes the method that is used for treating with Flt-3 and/or syk imbalance (deregulated) relevant disease, said method comprises at least a as above defined compound of treating significant quantity to the Mammals of this treatment of needs.
Be through regulation and control, regulate and/or suppress the disease that Flt-3 and/or syk are able to prevention, treatment or recovery (regresses) with the relevant disease of Flt-3 and/or syk imbalance.
Advantageously, can significant quantity use The compounds of this invention.This amount is usually included between every kg body weight 0.1mg-2g The compounds of this invention every day.
The present invention relates to method or the compound that is used at cell signal transduction being regulated and control, being regulated and/or suppresses on the other hand, said signal transduction by natural and/or the sudden change protein kinase, especially natural and/or the sudden change Tyrosylprotein kinase, more particularly natural and/or the sudden change Flt-3 and/or syk mediate.Said method comprises to cell and gives at least a The compounds of this invention.In one embodiment, said cell is hemopoietic stem cell or the AML parent cell with mutant protein kinase, especially tyrosine-kinase enzyme mutant, more particularly Flt-3 sudden change.
Term " The compounds of this invention " means that adopt, that comprise each embodiment alone or in combination above-mentioned oxazole derivatives.The arbitrary combination of different modification, aspect and embodiment is all within protection scope of the present invention.
The invention still further relates to and be used for method or compound that the humans and animals disease relevant with the signal transduction illness treated, said signal transduction is mediated by the protein kinase of natural and/or sudden change, the especially natural and/or Tyrosylprotein kinase of sudden change, Flt-3 and/or syk more particularly natural and/or sudden change.Particularly, these class methods are used to treat proliferative disorders, metabolic disorder, allergic conditions and/or degeneration illness.
Said method bag is to having the experimenter, the especially human patients that need to give at least a The compounds of this invention of significant quantity.
In one embodiment, said experimenter or patient are suffered from AML or ALL by diagnosis.
The present invention relates to be used to treat method or the compound of AML or ALL, said method comprises at least a The compounds of this invention that gives significant quantity to the experimenter who suffers from AML or ALL, especially human patients.
The present invention relates to be used to treat the method or the compound of hematopoietic disorder and malignant hematologic disease.
Particularly; The present invention is intended to the method that is used to treat disease; Said method comprises that the Mammals to this treatment of needs gives the above-claimed cpd of significant quantity, and said disease is selected from the group of being made up of following disease: autoimmune disease, allergic disease, bone loss (bone loss), cancer (like white blood disease and GIST), tumor vessel generation, virus infection, inflammatory diseases, inflammatory bowel (IBD), interstitial cystitis, mast cell disease, infection, metabolic disorder, cystic fibrosis, mellitus and CNS illness.
Above-claimed cpd can be used for making to the medicine of treating with Flt-3 and/or the relevant disease of syk imbalance, and said disease includes but not limited to:
-neoplastic disease is like mast cell disease, dog mastocytoma, solid tumor, human gastrointestinal tract's mesenchymoma (GIST), small cell lung cancer, nonsmall-cell lung cancer, acute myelogenous leukemia, acute lymphoblastic leukemia, myelodysplastic syndrome, chronic myelogenous leukemia (chronic myelogenous leukemia), colorectal carcinoma, cancer of the stomach, gastrointestinal stromal tumor, carcinoma of testis, glioblastoma multiforme, solid tumor and astrocytoma;
-tumor-blood-vessel growth;
-metabolic trouble is like mellitus and chronic complicating diseases, obesity, type ii diabetes, hyperlipidaemia and hyperlipemia, atherosclerosis, hypertension and cardiovascular disorder;
-allergic disease infects like asthma, rhinallergosis, allergic sinusitis, supersensitivity syndrome (anaphylactic syndrome), urticaria, angioedema, atopic dermatitis, contact dermatitis, erythema nodosum, erythema multiforme, cutaneous necrosis property trichodophlebitis (cutaneous necrotizing venulitis) and insect bite atopic dermatitis disease and blood-sucking parasites;
-interstitial cystitis;
-bone loss (osteoporosis);
-inflammatory diseases is like rheumatoid arthritis, conjunctivitis, rheumatoid spondylitis, osteo-arthritis, urarthritis and other arthritis feelings;
-autoimmune disease is like multiple sclerosis, psoriasis, inflammatory bowel disease, ulcerative colitis, Crohn disease, rheumatoid arthritis and polyarthritis, part and systemic scleroderma, systemic lupus erythematosus, discoid lupus erythematosus, cutaneous lupus (cutaneous lupus), dermatomyositis, polymyositis, siogren's syndrome, PAN, auto immune enteropathy and proliferative glomerulonephritis;
-transplant rejection or graft versus host disease in any organ transplantation (comprising kidney, pancreas, liver, heart, lung and marrow);
-other autoimmune disease that chronic active hepatitis and chronic fatigue syndrome of the present invention comprised;
Foaming illness under the-epidermis (subepidermal blistering disorders) is like pemphigus;
-vasculitis;
-virus infection;
-infectation of bacteria;
-melanocyte dysfunction relative disease; Excessive melanin pigmentation (hypermelanosis) as being caused by the melanocyte dysfunction comprises lentigo (lentigines), solar lentigo and senile lentigo, Dubreuilh melanosis, mole and malignant melanoma.About this point, the compound that the present invention comprises above-mentioned definition is used to make medicine that human skin bleaches or the purposes aspect the make-up composition in manufacturing;
-CNS illness is degenerated like mental illness, migraine, pain, the loss of memory and neurocyte.Particularly; The method of the invention is used to treat following illness: dysthymia disorders comprises dysthymic disorder, cyclothymic disorder, bipolar depression, severe depression or " melancholic temperament " depression, atypical depression, intractable depression, seasonal depression; Apositia; Exessive appetite; Syndrome before menstrual period; PMS (post-menopause syndrome); Other syndrome is like hyponea (mental slowing) and absent minded; Pessimistic worried (pessimistic worry); Exciting; The oneself belittles (self-deprecation); Sexual desire reduces; Pain comprises acute pain, post-operative pain, chronic pain, nociceptive pain, cancer pain, neuropathic pain, psychogenic pain syndrome; The anxiety illness comprises anxiety, phobia, obsession, posttraumatic stress disorder, acute stress disorder, the generalized-anxiety disorder relevant with overventilation and heart disorder; Such as the psychiatric emergency of panic attack (panic attacks), comprise psychological problem, DD, conversion disorder (conversion disorders), phobia, mania, delirium (delirium); Dissociative type outbreak (dissociative episode) comprises dissociative type amnesia, dissociative type fugue and dissociative type approval disease, depersonalization, catatonia, epilepsy (seizures); The major psychosis acute disease comprises suicide, self-ignorance, violence or Aggression, wound, borderline personality and acute psychological problem; Schizophrenia comprises paranoid schizophrenia, disorganized schizophrenia, catatonic schizophrenia and undifferentiated schizophrenia;
-nerve degenerative diseases comprises Alzheimer, parkinson's disease, Huntington's disease, prion disease, motor neuron (MND) and amyotrophic lateral sclerosis (ALS);
The substance use disorders that-this paper mentioned includes but not limited to drug habit, drug dependence, drug habituation, drug dependence, withdrawal symptom and overdose;
-cerebral ischemia;
-cystic fibrosis;
-Duchenne muscular dystrophy.
Therefore; The present invention relates to the purposes of one or more The compounds of this invention aspect the manufacturing medicine, said medicine is used to treat malignant hematologic disease, myeloproliferative illness, other proliferative disorders, autoimmune disorder, inflammatory diseases, allergic disease and/or sacred disease.
In embodiment, malignant hematologic disease be acute myelogenous leukemia (AML), myelodysplastic syndrome (MDS), acute lymphoblastic leukemia (ALL) and/or chronic lymphocytic leukemia (chronic myeloid leukemia) (CML).
In embodiment, proliferative disorders is a cancer.
In embodiment, autoimmune disorder is multiple sclerosis, psoriasis, inflammatory bowel disease, ulcerative colitis, Crohn disease, rheumatoid arthritis and polyarthritis, part and systemic scleroderma, systemic lupus erythematosus, discoid lupus erythematosus, cutaneous lupus, dermatomyositis, polymyositis, siogren's syndrome, PAN, auto immune enteropathy, atopic dermatitis and/or proliferative glomerulonephritis.
In embodiment, allergic disease is that asthma, rhinallergosis, allergic sinusitis, supersensitivity syndrome, urticaria, angioedema, atopic dermatitis, contact dermatitis, erythema nodosum, erythema multiforme, cutaneous necrosis property trichodophlebitis and insect bite atopic dermatitis disease and/or blood-sucking parasites infect.
In embodiment, sacred disease is Huntington's disease, schizophrenia, parkinson's disease and/or Alzheimer.
In embodiment, The compounds of this invention is used to make the medicine that plays the kinases inhibitor effect.
Particularly, said protein kinase is Flt-3 or syk.
The invention further relates to and be used to treat or prevent experimenter intravital protein kinase, especially Tyrosylprotein kinase, the method for Flt-3 and/or syk relative disease or illness more particularly, said method comprises at least a The compounds of this invention that gives significant quantity to the experimenter.
The present invention relates to pharmaceutical composition, said pharmaceutical composition comprises the combination of at least a The compounds of this invention and other molecular targeted reagent (molecularly targeted agent) significant quantity.
The present invention relates to be used to prevent or treat the method for malignant hematologic disease, myeloproliferative illness, other proliferative disorders, autoimmune disorder and skin disorder; Said method comprises: so that the amount of result of treatment enough to be provided, to there being the human or animal experimenter who needs simultaneously or in a sequence to give at least a The compounds of this invention combined with other molecular targeted reagent.
The present invention relates at least a The compounds of this invention together with other molecular targeted reagent in the purposes of making aspect the medicine, said medicine is used to treat malignant hematologic disease, myeloproliferative illness, other proliferative disorders, autoimmune disorder and skin disorder.
The invention still further relates to the purposes of at least a The compounds of this invention aspect selectivity inhibition syk.The invention still further relates to the purposes of at least a The compounds of this invention aspect treatment autoimmune disease and/or inflammatory diseases and/or allergic disease.
Embodiment
Next, through the embodiment that represents current preferred implementation the present invention is illustrated, said embodiment has constituted a part of the present invention, but by no means in order to limit scope of the present invention.
Embodiment 1 to preferred formula I compound is described below with embodiment 2:
Embodiment 001: (4-methyl-pyridine-2-yl)-[6-(2-styroyl-oxazoles-5-yl)-pyridine-2-yl]-amine
1H?NMR(DMSO-d
6,300MHz)δ=9.88(s,1H),8.12(d,J=5.0Hz,1H),7.90-7.41(m,4H),7.43-6.96(m,6H),6.78(d,J=4.8Hz,1H),3.26-2.92(m,4H),2.33(s,3H)。(ESI+)m/z?357(M+H)
+。
Embodiment 002: (4-methyl-pyridine-2-yl)-[3-(2-phenyl sulfenyl-oxazoles-5-yl)-phenyl]-amine
1H?NMR(DMSO-d
6,300MHz)δ=9.09(s,1H),8.02(d,J=5.0Hz,1H),7.93(s,1H),7.80-7.25(m,8H),8.02(d,J=7.4Hz,1H),6.64(br,2H),2.24(s,3H)。(ESI+)m/z?360(M+H)
+。RT=3.28min (method 1).
Embodiment 3-embodiment 7 to preferred formula II compound is described below:
Embodiment 003: (3-{2-[2-(4-methoxyl group-phenyl)-vinyl]-oxazoles-5-yl }-phenyl)-(4-methyl-pyridine-2-yl)-amine
1H?NMR(DMSO-d
6,300MHz)δ=9.12(s,1H),8.07(d,J=5.0Hz,1H),8.04(s,1H),7.80-7.60(m,4H),7.53(d,J=16.8Hz,1H),7.40-7.20(m,2H),7.05(d,J=16.8Hz,1H),7.00(d,J=8.1Hz,1H),6.68(s,1H),6.62(d,J=4.9Hz,1H),3.81(s,3H),2.25(s,3H)。(ESI+)m/z?384(M+H)
+。RT=3.34min (method 1).
Embodiment 004: (6-{2-[2-(4-methoxyl group-phenyl)-vinyl]-oxazoles-5-yl }-pyridine-2-yl)-(4-methyl-pyridine-2-yl)-amine
1H?NMR(DMSO-d
6,300MHz)δ=9.77(s,1H),8.11(d,J=4.8Hz,1H),7.92-7.52(m,7H),7.33(d,J=7.2Hz,1H),7.17-6.93(m,3H),6.78(d,J=4.7Hz,1H),3.81(s,3H),2.35(s,3H)。(ESI+)m/z?385(M+H)
+。
Embodiment 005: (4-methyl-pyridine-2-yl)-[6-(2-styryl-oxazoles-5-yl)-pyridine-2-yl]-amine
1H?NMR(DMSO-d
6,300MHz)δ=9.78(s,1H),8.12(d,J=5.0Hz,1H),7.86(s,1H),7.84-7.72(m,4H),7.72-7.56(m,2H),7.50-7.33(m,4H),7.25(d,J=16.5Hz,1H),6.78(d,J=4.9Hz,1H),2.35(s,3H)。(ESI+)m/z?355(M+H)
+。
Embodiment 006: pyridine-2-base-[6-(2-styryl-oxazoles-5-yl)-pyridine-2-yl]-amine
1H?NMR(DMSO-d
6,300MHz)δ=9.85(s,1H),8.25(d,J=4.6Hz,1H),8.00(d,J=8.4Hz,1H),7.90-7.56(m,7H),7.50-7.31(m,4H),7.25(d,J=16.4Hz,1H),6.92(m,1H)。(ESI+)m/z?341(M+H)
+。
Embodiment 007: (6-{2-[2-(4-methoxyl group-phenyl)-vinyl]-oxazoles-5-yl }-pyridine-2-yl)-pyridine-2-base-amine
1H?NMR(DMSO-d
6,300MHz)δ=9.84(s,1H),8.25(d,J=3.8Hz,1H),7.99(d,J=8.5Hz,1H),7.86-7.49(m,7H),7.33(d,J=7.3Hz,1H),7.09(d,J=16.4Hz,1H),7.01(d,J=8.4Hz,2H),6.96-6.89(m,1H),3.81(s,3H)。(ESI+)m/z?371(M+H)
+。
Embodiment 25-embodiment 31 to preferred formula III compound is described below:
Embodiment 025: (6-{2-[2,6-dimethyl--4-(2-morpholine-4-base-oxyethyl group)-phenyl]-oxazoles-5-yl }-pyridine-2-yl)-(4-methyl-pyridine-2-yl)-amine
1H?NMR(400MHz,DMSO)δ9.77(s,1H),8.11(d,J=5.1Hz,1H),7.84(s,2H),7.75(t,J=7.9Hz,1H),7.59(d,J=8.3Hz,1H),7.28(d,J=7.4Hz,1H),6.83(s,2H),6.77(d,J=5.2Hz,1H),4.16(t,J=5.7Hz,2H),3.60(t,J=4.7Hz,4H),3.33-3.29(m,4H),2.73(t,J=5.6Hz,2H),2.34-2.21(m,9H)。(ESI+)m/z?486(M+H)
+。RT=1.96min (method 1).
Embodiment 026: (5-chloro-pyridine-2-yl)-[6-(2-phenyl-oxazoles-5-yl)-pyridine-2-yl]-amine
(400MHz,DMSO)δ10.07(s,1H),8.29(d,J=2.6Hz,1H),8.18-8.08(m,3H),7.92(s,1H),7.91-7.79(m,2H),7.65-7.57(m,3H),7.54(d,J=8.4Hz,1H),7.45(d,J=7.4Hz,1H)。(ESI+)m/z?349(M+H)+。RT=4.64min (method 1).
Embodiment 027: (4-methyl-piperazine-1-yl)-(3-{5-[3-(4-methyl-pyridine-2-base is amino)-phenyl]-oxazoles-2-yl }-phenyl)-ketone
1H?NMR(400MHz,DMSO)δ9.15(s,1H),8.13(d,J=7.8Hz,1H),8.11-8.04(m,2H),8.02(s,1H),7.86-7.80(m,1H),7.79(s,1H),7.66(t,J=7.7Hz,1H),7.55(d,J=7.7Hz,1H),7.41-7.32(m,2H),6.69(s,1H),6.65(d,J=5.2Hz,1H),3.79-3.55(m,2H),3.47-3.35(m,2H),2.45-2.35(m,2H),2.34-2.27(m,2H),2.25(s,3H),2.20(s,3H)。(ESI+)m/z?454(M+H)
+。RT=1.90min (method 1).
Embodiment 028:3-(4-methyl-pyridine-2-base is amino)-5-(2-thiene-3-yl--oxazoles-5-yl)-cyanobenzene
1H?NMR(400MHz,DMSO)δ9.56(s,1H),8.35-8.33(m,1H),8.31(dt,J=2.7,1.2Hz,1H),8.23-8.21(m,1H),8.16(d,J=5.0Hz,1H),7.87(d,J=1.1Hz,1H),7.82-7.78(m,2H),7.66(dt,J=5.2,1.3Hz,1H),6.74(d,J=5.1Hz,1H),6.71(s,1H),2.28(s,3H)。(ESI+)m/z?359(M+H)
+。RT=3.57min (method 1).
Embodiment 029:4-{5-[6-(5-methyl-pyridine-2-base is amino)-pyridine-2-yl]-thiazol-2-yl }-cyanobenzene
1H?NMR(300MHz,DMSO)δ9.73(s,1H),8.65(s,1H),8.20(d,J=7.1Hz,2H),8.11(s,1H),8.03-7.93(m,3H),7.74(t,J=7.9Hz,1H),7.65(d,J=8.2Hz,1H),7.53(d,J=7.5Hz,1H),7.46(d,J=8.3Hz,1H),2.26(s,3H)。(APCI+)m/z?370(M+H)
+。RT=1.83min (method 2).
Embodiment 030:{6-[2-(4-methoxyl group-phenyl)-thiazole-5-yl]-pyridine-2-yl }-(6-methyl-pyridine-2-yl)-amine
1H?NMR(300MHz,DMSO)δ9.73(br?s,1H),8.47(s,1H),7.96(d,J=8.8Hz,2H),7.90(d,J=8.2Hz,1H),7.76-7.65(m,2H),7.47(d,J=8.2Hz,2H),7.10(d,J=8.8Hz,2H),6.81(d,J=7.2Hz,1H),3.85(s,3H),2.42(s,3H)。(APCI+)m/z?375(M+H)
+。RT=2.54min (method 2).
Embodiment 031: (4-methyl-pyridine-2-yl)-{ 3-[2-(3-trifluoromethyl-phenyl)-oxazoles-5-yl]-phenyl }-amine
1H?NMR(400MHz,DMSO)δ9.16(s,1H),8.36(d,J=7.7Hz,1H),8.31(s,1H),8.14(s,1H),8.07(d,J=5.2Hz,1H),7.94(d,J=8.0Hz,1H),7.89-7.75(m,3H),7.45-7.34(m,2H),6.69(s,1H),6.66(d,J=5.3Hz,1H),2.26(s,3H)。(ESI+)m/z?396(M+H)
+。RT=3.59min (method 1).
The embodiment that compound is synthetic
Following preparation embodiment will more fully understand the present invention through reference, but should said preparation embodiment be regarded as the qualification to scope of the present invention.Versatile content: the chemical of all uses all is a commercially available reagent level product.Solvent is anhydrous commercial grade, and need not to be further purified and directly use.Before using under argon stream fresh distillatory THF.Thin-layer chromatography through using precoating silica gel 60F 254 (Merck TLC plates) is monitored reaction process, and is in addition visual under UV light.
1Multiplicity in the H NMR spectrum is expressed as unimodal (s), wide unimodal (br s), bimodal (d), triplet (t), quartet (q) and multiplet (m), NMR spectrum Bruker300,360 or the 400MHz spectrograph in carry out.Carry out mass spectrum with positive ion mode or through APCI atmospheric pressure chemical ionization mass spectroscopy (APCI MS) with positive ion mode through electrospray ionization mass spectrometry (ESI MS).
LCMS method: method 1: be connected to this method of operation on the mass spectrometric ultra-high voltage liquid chromatography of TQD (UPLC) the ACQUITY Waters instrument.The gradient of using is: when t=0.0min to be in 5% CH in water+0.1% formic acid
3CN+0.1% formic acid is initial, until t=0.5min; Then, reach 100%CH from t=0.5min to t=7.0min with linear gradient
3CN+0.1% formic acid; Then, keep this state from t=7.0min to t=10.0min.The post that uses is Waters HSS C18 1.8 μ m, 2.1 * 50mm.The detecting instrument that uses is for using the triple quadrupole mass spectrograph (TQD) of ESI positive ion mode.
Method 2: be connected to this method of operation on the mass spectrometric HPLC 2695 Alliance Waters instruments of ZMD.The gradient of using is: at t=0.0min to be in the 0%CH in the water
3(10mM) is initial for CN+0.04% formic acid; Then, reach 100% CH when the t=3.1min with linear gradient
3CN+0.04% formic acid; Then, keep this state, be reduced to during to t=4.8min and contain 0% CH in the water to t=3.8min
3CN+0.04% formic acid.The post that uses is Sunfire2.1 * 50mm dp:3.5 μ m.The detecting instrument that uses is for using the triple quadrupole mass spectrograph (TQD) of APCI positive ion mode.
Abbreviation:
APCI+ APCI atmospheric pressure chemical ionization mass spectroscopy (positive ion mode)
BINAP 2,2 '-two (diphenylphosphine)-1,1 '-dinaphthalene
CDCl
3Deuterochloroform
The DCM methylene dichloride
DMF N, dinethylformamide
DMSO-d
6Six deuterated dimethyl sulfoxides
Dppbz 1, two (diphenylphosphine) benzene of 2-
ESI+ electrospray ionization mass spectrometry (positive ion mode)
EtOAc ETHYLE ACETATE
EtOH ethanol
H hour
K
2CO
3Salt of wormwood
LiOtBu trimethyl carbinol lithium
Two (trimethyl silane) acid amides lithiums of LiHMDS
MeOH methyl alcohol
MgSO
4Sal epsom
The NaI Soiodin
The NaOtBu sodium tert-butoxide
Ni (cod)
2Two (cyclooctadiene) nickel (0)
Pd
2(dba)
3Three (dibenzalacetone) palladium (0)
Pd (PPh
3)
4Tetrakis triphenylphosphine palladium (0)
SiO
2Silica gel
TosMIC tolysulfonyl ylmethyl isonitrile
The THF THF
Embodiment 008: the preparation of (4-methyl-pyridine-2-yl)-(6-oxazole-5-base-pyridine-2-yl)-amine
(5.90g 31.7mmol) adds K to 6-bromopyridine-2-formaldehyde in being in methyl alcohol (150ml) in stirred solution
2CO
3(5.25g, 38.0mmol) and TosMIC (7.43g, 38.0mmol).After stirring 1.5h at ambient temperature, mixture is concentrated under vacuum, make the product deposition through adding water.Solid by filtration is collected, and in vacuum drier in 50 ℃ down dry, obtain the 2-bromo-6-oxazole-5-yl pyridines compound (6.81g, 95% productive rate) of beige solid shape.
1H?NMR(CDCl
3,300MHz)：δ=7.97(s,1H),7.76(s,1H),7.65-7.57(m,2H),7.48-7.37(m,1H)。
In the ST that has the tetrafluoroethylene screw cap, pack into 2-bromo-6-oxazole-5-yl pyridines (4.00g, 17.8mmol), 2-amino-4-picoline (2.30g, 21.3mmol), Pd
2(dba)
3(320mg, 0.349mmol), (±)-BINAP (440mg, 0.707mmol), NaOtBu (2.40g, 25.0mmol) and dry toluene (80ml), and with being heated with stirring to 90 ℃ of following 1h.Cooled reaction mixture water is handled, and extracted with DCM.Organic phase after merging is used MgSO
4Carry out drying, filter also and under reduced pressure evaporate, pass through SiO then
2Column chromatography is carried out purifying with the 30%EtOAc wash-out that is in the hexanaphthene, obtains the title compound (1.89g, 42%) of orange/yellow solid shape.
1H?NMR(300MHz,DMSO-d
6)：δ=9.78(s,1H),8.53(s,1H),8.11(d,J=5.0Hz,1H),7.84-7.59(m,4H),7.25(d,J=7.3Hz,1H),6.76(d,J=5.0Hz,1H),2.32(s,3H)。(ESI+)m/z?253(M+H)。
The preparation of embodiment 009:4-(2-{5-[6-(4-methyl-pyridine-2-base amino)-pyridine-2-yl]-oxazoles-2-yl }-vinyl)-cyanobenzene
In ST, pack into (4-methyl-pyridine-2-yl)-(6-oxazole-5-base-pyridine-2-yl)-amine (200mg; 0.793mmol), 4-(2-bromo vinyl)-cyanobenzene (330mg; 1.59mmol), Pd (PPh3) 4 (46mg, 0.0396mmol), (127mg is 1.59mmol) with anhydrous 1 for LiOtBu; The mixture of 4-diox (5ml), and with being heated with stirring to 100 ℃ of following 2h.Cooled reaction mixture is used water treatment, and extract with DCM.Organic phase after merging is used MgSO
4Carry out drying, filter and vapourisation under reduced pressure, pass through SiO again
2Column chromatography is carried out purifying with the 50% EtOAc wash-out that is in the hexanaphthene, obtains the title compound (76mg, 25%) of yellow solid shape.
1H?NMR(300MHz,DMSO-d
6)δ=9.79(s,1H),8.12(d,J=5.1Hz,1H),7.97(d,J=8.3Hz,2H),7.90(d,J=8.2Hz,2H),7.86-7.61(m,5H),7.46(d,J=16.3Hz,1H),7.36(d,J=7.3Hz,1H),6.78(d,J=4.7Hz,1H),2.35(s,3H)。(ESI+)m/z?380(M+H)。
The preparation of embodiment 010:4-(2-{5-[6-(4-methyl-pyridine-2-base amino)-pyridine-2-yl]-oxazoles-2-yl }-ethyl)-cyanobenzene
Under envrionment temperature and pressure; In hydrogen atmosphere, will be in 4-among MeOH and the DCM (each 10ml) (2-{5-[6-(4-methyl-pyridine-2-base is amino)-pyridine-2-yl]-oxazoles-2-yl }-vinyl)-cyanobenzene (72mg, 0.189mmol) and the activated carbon mixture that carries 10% palladium (27mg) carry out vigorous stirring 24h.Add other catalyzer (27mg) and mixture is further stirred 18h.Mixture is filtered, under decompression, evaporate, grind with the DCM/ pentane then, obtain the title compound (32mg, 44%) of light yellow solid shape.
1H?NMR(300MHz,DMSO-d
6)δ9.75(s,1H),8.10(d,J=5.0Hz,1H),7.89-7.39(m,8H),7.17(d,J=7.2Hz,1H),6.73(t,J=13.6Hz,1H),3.22(s,4H),2.31(s,3H)。(ESI+)m/z?382(M+H)。
Embodiment 011: the preparation of (4-methyl-pyridine-2-yl)-[6-(2-pyridin-3-yl-oxazoles-5-yl)-pyridine-2-yl]-amine
By as above to 4-(2-{5-[6-(4-methyl-pyridine-2-base amino)-pyridine-2-yl]-oxazoles-2-yl }-vinyl)-cyanobenzene is said, use (4-methyl-pyridine-2-yl)-(6-oxazole-5-base-pyridine-2-yl)-amine, 3-bromopyridine, Pd (PPh
3)
4, LiOtBu and anhydrous 1, the 4-diox prepares, and obtains the title compound (8%) of light yellow solid shape.
1H?NMR(300MHz,DMSO-d
6)δ=9.81(s,1H),9.31(s,1H),8.76(d,J=4.8Hz,1H),8.46(d,J=8.1Hz,1H),8.12(d,J=5.0Hz,1H),7.91(s,2H),7.84-7.76(m,1H),7.69-7.52(m,2H),7.45(d,J=7.4Hz,1H),6.79(d,J=5.0Hz,1H),2.36(s,3H)。(ESI+)m/z330(M+H)。
Embodiment 032:N-(2-hydroxyl-ethyl)-N-methyl-3-{5-[6-(4-methyl-pyridine-2-base amino)-pyridine-2-yl]-oxazoles-2-yl }-preparation of benzsulfamide
By as above to 4-(2-{5-[6-(4-methyl-pyridine-2-base amino)-pyridine-2-yl]-oxazoles-2-yl }-vinyl)-cyanobenzene is said, use (4-methyl-pyridine-2-yl)-(6-oxazole-5-base-pyridine-2-yl)-amine, 3-bromo-N-(2-hydroxyl-ethyl)-N-methyl-benzsulfamide, Pd (PPh
3)
4, LiOtBu and anhydrous 1, the 4-diox prepares, and obtains the title compound (24%) of light yellow solid shape.
1HNMR(400MHz,CDCl
3)δ9.81(s,1H),8.45-8.34(m,2H),8.12(d,J=5.0Hz,1H),8.01-7.77(m,5H),7.66(d,J=8.4Hz,1H),7.46(d,J=7.4Hz,1H),6.79(d,J=5.0Hz,1H),4.83(t,J=5.5Hz,1H),3.55(q,J=5.8Hz,2H),3.11(t,J=5.9Hz,2H),2.81(d,J=8.0Hz,3H),2.36(s,3H)。(ESI+)m/z?466(M+H)
+。RT=2.45min (method 1).
Embodiment 033: the preparation of (4-methyl-pyridine-2-yl)-{ 6-[2-(3-tetramethyleneimine-1-ylmethyl-phenyl)-oxazoles-5-yl]-pyridine-2-yl }-amine hydrochlorate
To be in the 3-iodobenzene methyl alcohol (600mg among the DCM (3ml); 2.56mmol) solution is with THIONYL CHLORIDE 97 (3ml; 41.3mmol) handle and stir at ambient temperature 18h, further add then THIONYL CHLORIDE 97 (1ml, 13.7mmol) and reflux 12h.With cooled solution with 50% NaOH alkalize, dilute with water and extract with DCM.Organic phase after merging is used MgSO
4Carry out drying, filter and evaporate to dryness, obtain clarifying soup compound, said soup compound is left standstill the 3-iodine benzyl chloride (650mg, quantitative) that crystallization produces white solid.
(100mg, 0.396mmol) (0.5ml 6.02mmol) handles solution, and reflux 5h with tetramethyleneimine will to be in 3-iodine benzyl chloride in 1,4 diox (3ml).With cooled mixture evaporate to dryness, and handle with EtOAc and water.Organic phase is separated, use MgSO
4Carry out drying, filter and evaporate to dryness, obtain clarifying 1-(3-iodo-the benzyl)-tetramethyleneimine (110mg, 97%) of pulpous state.
Then; As above to 4-(2-{5-[6-(4-methyl-pyridine-2-base amino)-pyridine-2-yl]-oxazoles-2-yl }-vinyl)-cyanobenzene is said, use (4-methyl-pyridine-2-yl)-(6-oxazole-5-base-pyridine-2-yl)-amine (embodiment 008), 1-(3-iodo-benzyl)-tetramethyleneimine, Pd (PPh
3)
4, LiOtBu and anhydrous 1,4-diox preparation (4-methyl-pyridine-2-yl)-{ 6-[2-(3-tetramethyleneimine-1-ylmethyl-phenyl)-oxazoles-5-yl]-pyridine-2-yl }-amine.Place EtOAc also to handle the material after separating, after evaporated in vacuo, obtain the title compound (35%) of beige solid shape with HCl (2M is in the ether).
1H?NMR(400MHz,DMSO-d
6)δ12.65(s,1H),11.30(s,1H),8.53-8.47(m,2H),8.33(s,1H),8.19(d,J=7.6Hz,1H),8.07(t,J=7.9Hz,1H),7.85(d,J=7.8Hz,1H),7.80(d,J=7.6Hz,1H),7.67(t,J=7.7Hz,1H),7.52(s,1H),7.38(d,J=8.3Hz,1H),7.24(d,J=6.4Hz,1H),4.48(d,J=5.6Hz,2H),3.42-3.29(m,4H),2.51(s,3H),2.09-1.86(m,4H)。(ESI+)m/z?412(M+H)
+。RT=1.88min (method 1).
Embodiment 034: the preparation of (4-methyl-pyridine-2-yl)-{ 6-[2-(3-morpholine-4-ylmethyl-phenyl)-oxazoles-5-yl]-pyridine-2-yl }-amine hydrochlorate
Press as above to said 4-(3-iodo-the benzyl)-morpholine for preparing of 1-(3-iodo-benzyl)-tetramethyleneimine.Then; By as above to (4-methyl-pyridine-2-yl)-{ 6-[2-(3-tetramethyleneimine-1-ylmethyl-phenyl)-oxazoles-5-yl]-pyridine-2-yl }-amine hydrochlorate is said, use (4-methyl-pyridine-2-yl)-(6-oxazole-5-base-pyridine-2-yl)-amine (embodiment 008), 4-(3-iodo-benzyl)-morpholine, Pd (PPh
3)
4, LiOtBu and anhydrous 1; The 4-diox, next use HCl (2M; Be in the ether) prepare (4-methyl-pyridine-2-yl)-{ 6-[2-(3-morpholine-4-ylmethyl-phenyl)-oxazoles-5-yl]-pyridine-2-yl }-amine, obtain the title compound (8%) of beige solid shape.
1H?NMR(400MHz,DMSO-d
6)δ12.69-11.90(m,1H),11.90-11.22(m,1H),8.51(s,1H),8.46(d,J=5.8Hz,1H),8.28(s,1H),8.22(d,J=7.7Hz,1H),8.05(t,J=7.9Hz,1H),7.85(d,J=7.5Hz,1H),7.75(d,J=7.7Hz,1H),7.70(t,J=7.7Hz,1H),7.57(s,1H),7.41(d,J=8.3Hz,1H),7.19(d,J=4.5Hz,1H),4.47(s,2H),3.95(d,J=11.8Hz,2H),3.85(t,J=11.8Hz,2H),3.27(d,J=11.8Hz,2H),3.20-3.10(m,2H),2.50(s,3H)。(ESI+)m/z?428(M+H)
+。RT=1.80min (method 1).
Embodiment 012: the preparation of [6-(2-chlorine-oxazoles-5-yl)-pyridine-2-yl]-(4-methyl-pyridine-2-yl)-amine
Under argon gas atmosphere; To be in distillatory dry THF (50ml) (4-methyl-pyridine-2-yl)-(6-oxazole-5-base-pyridine-2-yl)-(embodiment 008 for amine; 1.00g 3.96mmol) solution after the stirring is cooled to-78 ℃, drips LiHMDS (1M then; Be among the THF) (5.96ml 5.96mmol) handles.After stirring 15min under-78 ℃, use C
2Cl
6(1.41g 5.96mmol) disposablely handles solution, and reaction is back under the envrionment temperature.Then, with extremely-78 ℃ of reaction cooled, and (5.96ml 5.96mmol), uses C again to drip LiHMDS (1M is among the THF)
2Cl
6(1.41g 5.96mmol) handles, and is warming up to room temperature and stirs 1h.The mixture water is handled, and extracted with DCM.Organic phase after merging is used MgSO
4Carry out drying, filter also evaporate to dryness under reduced pressure, pass through SiO again
2Column chromatography is carried out purifying with the 30% EtOAc wash-out that is in the hexanaphthene, obtains the title compound (836mg, 74%) of pale solid shape.
1H?NMR(300MHz,DMSO-d
6)δ=9.82(s,1H),8.10(d,J=5.0Hz,1H),7.84-7.63(m,4H),7.24(d,J=7.0Hz,1H),6.76(d,J=4.6Hz,1H),2.31(s,3H)。
Embodiment 035: the preparation of (5-chloro-pyridine-2-yl)-[6-(2-thiene-3-yl--oxazoles-5-yl)-pyridine-2-yl]-amine
Through as the above-mentioned same reaction sequence that is used for preparing [6-(2-chlorine-oxazole-5-yl)-pyridine-2-yl]-(4-methyl-pyridine-2-yl)-amine (embodiment 012); Prepare [6-(2-chlorine-oxazoles-5-yl)-pyridine-2-yl]-(5-chloro-pyridine-2-yl)-amine, use LiHMDS and C at last
2Cl
6Carry out chlorination, chloro-oxazoles that obtain expecting.
To be in [6-(2-chlorine-oxazoles-5-yl)-pyridine-2-yl]-(5-chloro-pyridine-2-yl)-amine in THF (4ml) and the water (2ml) (50mg, 0.162mmol) solution with 3 thienylboronic acid (25mg, 0.195mmol), Pd (PPh
3)
4(19mg, 0.0162mmol) and K
2CO
3(50mg 0.358mmol) after the processing, is heated to 100 ℃ of following 60h.Cooled mixture water is handled, and extracted with DCM.Organic phase after merging is used MgSO
4Carry out drying, filter also evaporate to dryness under reduced pressure, pass through SiO again
2Column chromatography is carried out purifying with the 1%EtOH wash-out that is among the DCM, obtains the title compound (51mg, 89%) of pale solid shape.
1H?NMR(400MHz,DMSO-d
6)δ10.05(s,1H),8.33-8.31(m,1H),8.28(d,J=2.5Hz,1H),8.15(d,J=9.0Hz,1H),7.89(dd,J=9.0,2.7Hz,1H),7.85(s,1H),7.83-7.77(m,2H),7.69-7.65(m,1H),7.49(d,J=8.3Hz,1H),7.40(d,J=7.4Hz,1H)。(ESI+)m/z?355(M+H)
+。RT=4.28min (method 1).
Embodiment 036:{6-[2-(1H-indoles-5-yl)-oxazoles-5-yl]-pyridine-2-yl }-preparation of pyrazine-2-base-amine
Press as above to (5-chloro-pyridine-2-yl)-[6-(2-thiene-3-yl--oxazoles-5-yl)-pyridine-2-yl]-amine is said, by [6-(the 2-chlorine-oxazoles-5-yl)-pyridine-2-yl]-pyrazine-2-base-amine, indoles-5-boric acid, the Pd (PPh that are in the THF/ water
3)
4And K
2CO
3Prepare, the title compound of beige solid shape is provided.
1H?NMR(400MHz,DMSO-d
6)δ11.37(s,1H),10.08(s,1H),9.28(s,1H),8.38(s,1H),8.30-8.25(m,1H),8.16(d,J=2.6Hz,1H),7.93-7.81(m,2H),7.79(s,1H),7.65(d,J=8.3Hz,1H),7.58(d,J=8.5Hz,1H),7.51-7.42(m,2H),6.62(s,1H)。(ESI+)m/z?338(M+H)
+。RT=1.81min (method 1).
Embodiment 037:{6-[2-(1H-indoles-5-yl)-oxazoles-5-yl]-5-methyl-pyridine-2-yl }-preparation of (4-methyl-pyridine-2-yl)-amine
Through the method (J.Org.Chem., 2005,8220) of Gros P. and Fort Y., prepare 2-bromo-6-chloro-3-methyl-pyridine by 2-chloro-5-picoline.Under argon gas; Under-78 ℃, drip and be in the 2-bromo-6-chloro-3-methyl-pyridine (642mg in the dry THF (4ml); 3.10mmol), to being in n-BuLi (1.6M is in the hexane) (2.0ml in the dry THF (6ml); 3.30mmol) solution handles, and under this temperature, stir 30min.Dropping is in DMF solution in the dry THF (1ml), and (385 μ l 4.70mmol), and further stir 45min down at-78 ℃, are warming up to envrionment temperature then.To react quencher, extract with water treatment and with EtOAc with MeOH (3ml).Organic phase after merging is used MgSO
4Carry out drying, filter also evaporate to dryness under reduced pressure, pass through SiO again
2Column chromatography is carried out purifying with the 2%EtOH wash-out that is among the DCM, obtains the 6-chloro-3-methyl-pyridine-2-formaldehyde (217mg, 45%) of yellow solid shape.
1H?NMR(400MHz,CDCl
3)δ10.09(s,1H),7.60(d,J=7.7Hz,1H),7.42(d,J=7.7Hz,1H),2.64(s,3H)。
Then; Through as the above-mentioned same reaction sequence that is used for preparing [6-(2-chlorine-oxazole-5-yl)-pyridine-2-yl]-(4-methyl-pyridine-2-yl)-amine prepare [6-(2-chlorine-oxazole-5-yl)-5-methyl-pyridine-2-yl]-(4-methyl-pyridine-2-yl)-amine, use LiHMDS and C at last
2Cl
6Carry out chlorination, chloro-oxazoles that obtain expecting, said Lv Dai oxazole directly uses and need not to be further purified.
Then; By as above to (5-chloro-pyridine-2-yl)-[6-(2-thiene-3-yl--oxazoles-5-yl)-pyridine-2-yl]-amine is said, use to be in (5-chloro-pyridine-2-yl)-[6-(2-thiene-3-yl--oxazoles-5-yl)-pyridine-2-yl]-amine, indoles-5-boric acid, the Pd (PPh in the THF/ water
3)
4And K
2CO
3Prepare { 6-[2-(1H-indoles-5-yl)-oxazoles-5-yl]-5-methyl-pyridine-2-yl }-(4-methyl-pyridine-2-yl)-amine, obtain { 6-[2-(1H-indoles-5-yl)-oxazoles-5-yl]-5-methyl-pyridine-2-yl }-(4-methyl-pyridine-2-the yl)-amine (32%) of beige solid shape.
1H?NMR(400MHz,DMSO-d
6)δ11.45(s,1H),9.62(s,1H),8.36(s,1H),8.14(s,1H),8.11(d,J=5.1Hz,1H),7.90(dd,J=8.5,1.5Hz,1H),7.72(s,1H),7.65-7.54(m,2H),7.51-7.46(m,1H),7.40(d,J=8.4Hz,1H),6.77(d,J=4.9Hz,1H),6.61(s,1H),2.51(s,3H),2.39(s,3H).(ESI+)m/z?382(M+H)
+。RT=2.98min (method 1).
Embodiment 013: the preparation of [6-(2-cyclohexyl sulfenyl-oxazoles-5-yl)-pyridine-2-yl]-(4-methyl-pyridine-2-yl)-amine
To be in [6-(2-chlorine-oxazoles-5-yl)-pyridine-2-yl]-(4-methyl-pyridine-2-yl)-amine among the iPrOH (5ml) (50mg, 0.174mmol), K
2CO
3(72mg is 0.523mmol) with hexanaphthene mercaptan (64 μ l, mixture heating up backflow 18h 0.523mmol).Cooled mixture water is handled, and extracted with DCM.Organic phase after merging is used MgSO
4Carry out drying, filter and under reduced pressure evaporate to dryness to yellow jelly.Said jelly is positioned among the DCM of minimum quantity, and precipitates, obtain the title compound (45mg, 71%) of beige solid shape with Skellysolve A.
1H?NMR(300MHz,DMSO-d
6)δ9.76(s,1H),8.10(s,1H),7.56-7.78(m,4H),7.17(d,J=5.9Hz,1H),6.75(s,1H),3.71(m,1H),2.31(s,3H),2.08(m,2H),1.64(m,8H)。(ESI+)m/z?367(M+H)
+。
Embodiment 014:5-[6-(4-picoline-2-base the is amino) pyridine-2-yl]-N-(preparation of pyridin-4-yl methyl) oxazole-2-amine
(50mg, 0.174mmol) solution is handled with 4-aminomethyl pyridine (53 μ l), and reflux 40h will to be in [6-(2-chlorine-oxazoles-5-yl)-pyridine-2-yl]-(4-methyl-pyridine-2-yl)-amine among the iPrOH (5ml).Cooled mixture water is handled, and extracted with DCM.Organic phase after merging is used MgSO
4Carry out drying, filter also evaporate to dryness under reduced pressure, pass through Al again
2O
3Column chromatography (Brockman grade III, 7% H
2O) carry out purifying with the 2% EtOH wash-out that is among the DCM.Precipitate from DCM with Skellysolve A, obtain the title compound (34mg, 55%) of pale yellow solid-like.
1H?NMR(300MHz,DMSO-d
6)δ9.61(s,1H),8.52(d,J=4.6Hz,2H),8.25(t,J=5.8Hz,1H),8.08(d,J=5.0Hz,1H),7.73(s,1H),7.64(t,J=7.9Hz,1H),7.47(d,J=8.3Hz,1H),7.36(d,J=4.9Hz,2H),7.29(s,1H),6.92(d,J=7.6Hz,1H),6.73(d,J=5.0Hz,1H),4.49(d,J=5.7Hz,2H),2.29(s,3H)。(ESI+)m/z?359(M+H)
+。
Embodiment 015:N-(the 4-methoxy-benzyl)-5-[preparation of 6-(4-picoline-2-base is amino) pyridine-2-base] oxazole-2-amine
By as above [6-(4-picoline-2-base is amino) pyridine-2-yl]-(pyridin-4-yl methyl) oxazole-2-amine is said, prepares said compound by the Lv Dai oxazole and the 4-methoxy-benzyl amine that are among the iPrOH for N-to 5-.
1H?NMR(300MHz,DMSO-d
6)δ9.60(s,1H),8.18-8.00(m,2H),7.75(s,1H),7.63(t,J=7.9Hz,1H),7.45(d,J=8.3Hz,1H),7.38-7.24(m,3H),6.95-6.86(m,3H),6.73(d,J=5.0Hz,1H),4.37(d,J=5.9Hz,2H),3.72(s,3H),2.30(s,3H)。(ESI+)m/z?388(M+H)
+。
Embodiment 038:4-{5-[6-(5-methyl-thiazol-2-yl amino)-pyridine-2-yl]-oxazoles-2-yl }-preparation of piperazine-2-ketone
By as above [6-(4-picoline-2-base is amino) pyridine-2-yl]-(pyridin-4-yl methyl) oxazole-2-amine is said, prepares said compound by [6-(2-chlorine-oxazoles-5-yl)-pyridine-2-yl]-(5-methyl-thiazol-2-yl)-amine and the 2-oxo piperazine that are among the iPrOH for N-to 5-.
1H?NMR(400MHz,DMSO-d
6)δ11.08(s,1H),8.14(s,1H),7.68(t,J=7.9Hz,1H),7.59(s,1H),7.16-6.97(m,2H),6.83(d,J=8.2Hz,1H),4.11(s,2H),3.86-3.63(m,2H),3.43-3.32(m,2H),2.37(s,3H)。(ESI+)m/z?357(M+H)
+。RT=1.91min (method 1).
Embodiment 039:{6-[2-(4-methyl-piperazine-1-yl)-oxazoles-5-yl]-pyridine-2-yl }-preparation of (3-trifluoromethyl-phenyl)-amine
By as above [6-(4-picoline-2-base is amino) pyridine-2-yl]-(pyridin-4-yl methyl) oxazole-2-amine is said, prepares said compound by [6-(2-chlorine-oxazoles-5-yl)-pyridine-2-yl]-(3-trifluoromethyl-phenyl)-amine and the N methyl piperazine that are among the iPrOH for N-to 5-.
1H?NMR(400MHz,DMSO-d
6)δ9.54(s,1H),8.66(s,1H),7.72(d,J=8.0Hz,1H),7.63(t,J=7.9Hz,1H),7.50(t,J=7.9Hz,1H),7.36(s,1H),7.21(d,J=7.5Hz,1H),7.00(d,J=7.5Hz,1H),6.70(d,J=8.3Hz,1H),3.58-3.48(m,4H),2.46-2.37(m,4H),2.23(s,3H)。(ESI+)m/z?404(M+H)
+。RT=3.01min (method 1).
Embodiment 040: the preparation of (6-{2-[4-(2-methoxyl group-ethyl)-piperazine-1-yl]-oxazoles-5-yl }-pyridine-2-yl)-(4-methyl-pyridine-2-yl)-amine
(1.00g, 5.31mmol) solution is used K will to be in N-Boc-piperazine in the acetonitrile (30ml)
2CO
3(2.20g, 15.9mmol) (812 μ l 5.84mmol) handle, and are heated to 80 ℃ of following 18h with (2-bromotrifluoromethane) methyl ether.Cooled mixture water is diluted, and extract with DCM.Organic phase after merging is used MgSO
4Carry out drying, filter and evaporation, again resistates is passed through SiO
2Column chromatography is carried out purifying with the 5%EtOH wash-out that is among the DCM, obtains clarifying buttery 1-Boc-4-(2-methoxyl group-ethyl)-piperazine (978mg, 76%).
1H?NMR(400MHz,DMSO-d
6)δ3.41(t,J=5.8Hz,2H),3.29-3.25(m,4H),3.21(s,3H),2.45(t,J=5.8Hz,2H),2.33(t,J=5.0Hz,4H),1.38(s,9H)。
(264mg, solution 1.08mmol) is handled with TFA (1ml), and stirs 2h at ambient temperature will to be in 1-Boc-4-(2-methoxyl group-ethyl)-piperazine among the DCM (10ml).With said solution evaporate to dryness, the crude mixture that contains 1-(2-methoxyl group-ethyl)-piperazine trifluoroacetate directly uses and need not to be further purified.
Then; By as above (pyridin-4-yl methyl) oxazole-2-amine is said, prepares (6-{2-[4-(2-methoxyl group-ethyl)-piperazine-1-yl]-oxazoles-5-yl }-pyridine-2-yl)-(4-methyl-pyridine-2-yl) amine by being in [6-(2-chlorine-oxazoles-5-yl)-pyridine-2-yl]-(4-methyl-pyridine-2-yl)-amine and 1-(2-methoxyl group-ethyl)-piperazine trifluoroacetate among the iPrOH to 5-[6-(4-picoline-2-base amino) pyridine-2-yl]-N-.
1H?NMR(400MHz,DMSO-d
6)δ9.59(s,1H),8.08(d,J=5.1Hz,1H),7.86(s,1H),7.63(t,J=8.0Hz,1H),7.41-7.36(m,2H),7.03(d,J=7.4Hz,1H),6.73(d,J=4.9Hz,1H),3.52(t,J=4.7Hz,4H),3.47(t,J=5.7Hz,2H),3.25(s,3H),2.63-2.52(m,6H),2.30(s,3H)。(ESI+)m/z?395(M+H)
+。RT=1.54min (method 1).
Embodiment 041:1-(2-methoxyl group-ethyl)-4-{5-[3-(4-methyl-pyrimidine-2--amino)-phenyl]-oxazoles-2-yl }-preparation of piperazine-2-ketone
By as above [6-(4-picoline-2-base is amino) pyridine-2-yl]-(pyridin-4-yl methyl) oxazole-2-amine is said, is prepared by [3-(2-chlorine-oxazoles-5-yl)-phenyl]-(4-methyl-pyrimidine-2-base)-amine and 1-(2-methoxyl group-ethyl)-2-oxo piperazine trifluoroacetate that are among the iPrOH for N-to 5-.
1H?NMR(400MHz,DMSO-d
6)δ9.56(s,1H),8.35(d,J=5.0Hz,1H),8.10(s,1H),7.64(d,J=8.0Hz,1H),7.31-7.20(m,2H),7.15(d,J=7.6Hz,1H),6.76(d,J=5.0Hz,1H),4.10(s,2H),3.79-3.72(m,2H),3.58-3.46(m,6H),3.25(dd,J=2.7,2.2Hz,3H),2.38(s,3H)。(ESI+)m/z?409(M+H)
+。RT=2.94min (method 1).
Embodiment 042:3-{2-[(2-methoxyl group-ethyl)-methyl-amino]-oxazoles-5-yl }-preparation of 5-(4-methyl-pyridine-2-base amino)-cyanobenzene
By as above [6-(4-picoline-2-base is amino) pyridine-2-yl]--oxazoles-2-amine is said for N-(pyridin-4-yl methyl) to 5-, prepare by 3-(2-chlorine-oxazoles-5-yl)-5-(4-methyl-pyridine-2-base the is amino)-cyanobenzene and N-(2-methoxy ethyl) methylamine that are among the iPrOH.(400MHz,DMSO-d
6)δ9.38(s,1H),8.18(d,J=1.7Hz,1H),8.10(d,J=5.1Hz,1H),7.87(t,J=1.7Hz,1H),7.49(t,J=1.4Hz,1H),7.41(s,1H),6.70(d,J=5.3Hz,1H),6.68(s,1H),3.64-3.60(m,2H),3.60-3.55(m,2H),3.29(s,3H),3.11(s,3H),2.26(s,3H)。(ESI+)m/z?364(M+H)
+。RT=2.55min (method 1).
Embodiment 016: the preparation of (4-methyl-pyridine-2-yl)-[6-(2-pyridine-2-base-oxazoles-5-yl)-pyridine-2-yl]-amine
To be in [6-(2-chlorine-oxazoles-5-yl)-pyridine-2-yl]-(4-methyl-pyridine-2-yl)-amine in the toluene (4ml) (44mg, 0.153mmol), 2-three normal-butyl stannyl pyridines (68mg, 0.184mmol) and Pd (PPh
3)
4(18mg, mixture heating up backflow 18h 0.016mmol) concentrate then in a vacuum.Resistates is passed through SiO
2Column chromatography is carried out purifying with the 5%EtOH wash-out that is among the DCM, obtains the title compound (16mg, 31%) of greenish orange look solid-like.
1H?NMR(300MHz,DMSO-d
6)：δ=9.85(s,1H),8.76(d,J=5.0Hz,1H),8.21(d,J=7.8Hz,1H),8.12(d,J=5.0Hz,1H),8.03(t,J=7.8Hz,1H),7.94(s,1H),7.91(s,1H),7.80(t,J=7.8Hz,1H),7.67(d,J=8.5,1H),7.58(m,1H),7.39(d,J=7.2Hz,1H),6.78(d,J=5.0Hz,1H),2.38(s,3H)。(ESI+)m/z?330(M+H)
+。RT=2.29min (method 1).
Embodiment 017: the preparation of [6-(2-iodine-oxazoles-5-yl)-pyridine-2-yl]-(4-methyl-pyridine-2-yl)-amine
Press as above to [6-(2-chlorine-oxazoles-5-yl)-pyridine-2-yl]-(4-methyl-pyridine-2-yl)-amine is said; By the ethylidene periodide, LiHMDS (the 1M solution that are among the anhydrous THF; Be among the THF) and (4-methyl-pyridine-2-yl)-(6-oxazole-5-base-pyridine-2-yl)-amine prepare 2-Dian Dai oxazole verivate, through SiO
2After column chromatography uses the 40%EtOAc wash-out that is in the hexanaphthene to carry out purifying, produce the title compound (41%) of yellow solid shape.
1H?NMR(300MHz,DMSO-d
6)δ=9.81(s,1H),8.10(d,J=5.0Hz,1H),7.84-7.51(m,4H),7.23(d,J=7.2Hz,1H),6.77(d,J=4.6Hz,1H),2.33(s,3H)。
Embodiment 018: the preparation of (4-methyl-pyridine-2-yl)-[6-(2-phenyl-oxazoles-5-yl)-pyridine-2-yl]-amine
To be in [6-(2-iodine-oxazoles-5-yl)-pyridine-2-yl]-(4-methyl-pyridine-2-yl)-amine in THF (4ml) and water (2ml) mixture (46mg, 0.121mmol), phenyl-boron dihydroxide (30mg, 0.246mmol), K
2CO
3(37mg, 0.268mmol) and Pd (PPh
3)
4(14mg, solution 0.012mmol) stirs 18h down at 90 ℃.Cooled reaction mixture water is handled, and extracted with EtOAc.Organic phase after merging is used MgSO
4Carry out drying, behind filtration and the vapourisation under reduced pressure, through SiO
2Column chromatography is carried out purifying with the 30%EtOAc wash-out that is in the hexanaphthene, obtains the title compound (30mg, 75%) of greenish orange look solid-like.
1H?NMR(DMSO-d
6,300MHz)：δ=9.79(s,1H),8.12(m,2H),8.02(s,1H),7.93(s,1H),7.86(s,1H),7.78(m,2H),7.58(m,2H),7.40(t,J=7.0Hz,1H),7.33(t,J=7.0Hz,1H),6.78(d,J=5.0Hz,1H),2.37(s,3H)。(ESI+)m/z?329(M+H)
+。RT=2.84min (method 1).
Embodiment 043: the preparation of (4-methyl-pyridine-2-yl)-(3-{2-[2-(3-trifluoromethyl-phenyl)-vinyl]-oxazoles-5-yl }-phenyl)-amine
By as above to (4-methyl-pyridine-2-yl)-[6-(2-phenyl-oxazoles-5-yl)-pyridine-2-yl]-amine is said, use [3-(2-iodine-oxazoles-5-yl)-phenyl]-(4-methyl-pyridine-2-yl)-amine, trans-2-(3-trifluoromethyl) vinyl boric acid, K in 2:1 (volume ratio) mixture that is in THF and water
2CO
3And Pd (PPh
3)
4Prepare said compound, thereby (the 4-methyl-pyridine-2-yl) of generation light yellow solid shape-(3-{2-[2-(3-trifluoromethyl-phenyl)-vinyl]-oxazoles-5-yl }-phenyl)-amine (72%).
1H?NMR(400MHz,DMSO-d
6)δ9.26-8.94(m,1H),8.15(s,J=8.6Hz,1H),8.11-8.06(m,3H),7.76-7.63(m,5H),7.43(d,J=16.5Hz,1H),7.40-7.29(m,2H),6.68(s,1H),6.64(d,J=5.2Hz,1H),2.25(s,3H)。(ESI+)m/z?422(M+H)
+。RT=3.84min (method 1).
Embodiment 044:{6-[2-(2-methoxyl group-pyridin-3-yl)-oxazoles-5-yl]-pyridine-2-yl }-preparation of (4-methyl-pyridine-2-yl)-amine
By as above to (4-methyl-pyridine-2-yl)-[6-(2-phenyl-oxazoles-5-yl)-pyridine-2-yl]-amine is said, use [6-(2-iodine-oxazoles-5-yl)-pyridine-2-yl]-(4-methyl-pyridine-2-yl)-amine, 2-methoxyl group-pyridine-3-boric acid, K in 2:1 (volume ratio) mixture that is in THF and water
2CO
3And Pd (PPh
3)
4Prepare, produce { 6-[2-(2-methoxyl group-pyridin-3-yl)-oxazoles-5-yl]-pyridine-2-yl }-(4-methyl-pyridine-2-the yl)-amine of yellow solid shape.
1H?NMR(400MHz,DMSO-d
6)δ9.76(s,1H),8.46-8.31(m,2H),8.12(d,J=5.0Hz,1H),7.87-7.82(m,2H),7.82-7.75(m,1H),7.63(d,J=8.4Hz,1H),7.34(d,J=7.3Hz,1H),7.21(dd,J=7.5,5.0Hz,1H),6.78(d,J=5.0Hz,1H),4.04(s,3H),2.33(s,3H)。(ESI+)m/z?360(M+H)
+。RT=2.54min (method 1).
Embodiment 045:3-{5-[6-(4-methyl-pyridine-2-base amino)-pyridine-2-yl]-oxazoles-2-yl }-preparation of 1H-pyridin-2-ones
The solution that will be in above-mentioned { 6-[2-(2-methoxyl group-pyridin-3-yl)-oxazoles-5-yl]-pyridine-2-yl }-(4-methyl-pyridine-2-the yl)-amine among the EtOH (10ml) is handled with dense HCl (1ml), and is heated to 80 ℃ of following 3h then to 60 ℃ of following heating 18h.Cooled mixture water is handled, and be settled out the product of yellow solid shape.
1H?NMR(400MHz,DMSO-d
6)δ12.23(s,1H),9.78(s,1H),8.29-8.22(m,1H),8.11(d,J=5.0Hz,1H),7.86(s,1H),7.82-7.73(m,2H),7.69-7.63(m,1H),7.60(d,J=8.4Hz,1H),7.29(d,J=7.4Hz,1H),6.77(d,J=5.0Hz,1H),6.40(t,J=6.7Hz,1H),2.35(s,3H)。(ESI+)m/z?346(M+H)
+。RT=2.02min (method 1).
Embodiment 046:3-{5-[6-(4-methyl-pyridine-2-base amino)-pyridine-2-yl]-oxazoles-2-yl }-preparation of 1-(2-morpholine-4-base-ethyl)-1H-pyridin-2-ones
To be in above-mentioned 3-{5-among the DMF (6ml) [6-(4-methyl-pyridine-2-base is amino)-pyridine-2-yl]-oxazoles-2-yl }-the 1H-pyridin-2-ones (60mg, 0.17mmol), 1-(2-chloroethyl) morpholine (36mg, 0.19mmol), K
2CO
3(29mg, 0.21mmol), NaI (29mg, ℃ following 18h of mixture heating up to 50 0.19mmol).Mixture is concentrated under vacuum, and the resistates water is handled, extract with EtOAc again.Organic phase water after merging is washed, use MgSO
4Carry out drying, filter and vapourisation under reduced pressure, pass through Al again
2O
3Column chromatography (Brockman grade III, 7% H
2O) carry out purifying with the 2%EtOH wash-out that is among the DCM, obtain the title compound (27mg, 35%) of light yellow solid shape.
1H?NMR(400MHz,DMSO-d
6)δ9.77(s,1H),8.23(dd,J=7.2,2.0Hz,1H),8.11(d,J=5.1Hz,1H),7.95(dd,J=6.6,2.0Hz,1H),7.89(s,1H),7.83-7.72(m,2H),7.58(d,J=8.4Hz,1H),7.29(d,J=7.4Hz,1H),6.77(d,J=5.0Hz,1H),6.43(t,J=6.9Hz,1H),4.13(t,J=6.2Hz,2H),3.56(t,J=4.3Hz,4H),2.62(t,J=6.2Hz,2H),2.48-2.40(m,4H),2.35(s,3H)。(ESI+)m/z459(M+H)
+。RT=1.63min (method 1).
Embodiment 047: the preparation of (4-methyl-pyridine-2-yl)-[6-(2-phenylacetylene base-oxazoles-5-yl)-pyridine-2-yl]-amine
In the ST that has the tetrafluoroethylene screw cap, pack into and be in (4-methyl-pyridine-2-yl)-(6-oxazole-5-base-pyridine-2-yl)-amine (200mg in the dry diox (5ml); 0.793mmol), bromoacetylene base benzene (172mg, 0.951mmol), Ni (cod)
2(11mg, 0.040mmol), dppbz (18mg, 0.040mmol) and LiOtBu (127mg, mixture 1.59mmol), and be heated to 100 ℃ of following 2h.Again to wherein adding bromoacetylene base benzene (172mg), Ni (cod)
2(11mg), (127mg 1.59mmol) with dry diox (2ml), and continues heating 36h for dppbz (18mg), LiOtBu.Cooled mixture water is handled, and extracted with DCM.Organic phase after merging is used MgSO
4Carry out drying, filter and vapourisation under reduced pressure, pass through SiO again
2Column chromatography is carried out purifying with the 30%EtOAc wash-out that is in the hexanaphthene, obtains the title compound (35mg, 13%) of pale solid shape.
1H?NMR(400MHz,DMSO-d
6)δ9.80(s,1H),8.11(d,J=5.1Hz,1H),7.87(s,J=26.8Hz,1H),7.80-7.69(m,5H),7.60-7.49(m,3H),7.33(d,J=7.2Hz,1H),6.77(d,J=5.1Hz,1H),2.33(s,3H)。(ESI+)m/z?353(M+H)
+。RT=3.24min (method 1).
Embodiment 048: the preparation of [6-(2-benzoxazole-2-base-oxazoles-5-yl)-pyridine-2-yl]-(4-methyl-pyridine-2-yl)-amine
In the ST that has the tetrafluoroethylene screw cap, pack into and be in [6-(2-iodine-oxazoles-5-yl)-pyridine-2-yl]-(4-methyl-pyridine-2-yl)-amine (100mg in the dry diox (5ml); 0.264mmol), benzoxazole (31mg, 0.264mmol), Pd (PPh
3)
4(15mg, 0.013mmol) and LiOtBu (42mg, mixture 0.529mmol), and be heated to 100 ℃ of following 24h.Cooled mixture water is handled, and extracted with DCM.Organic phase after merging is used MgSO
4Carry out drying, filter and vapourisation under reduced pressure, pass through SiO again
2Column chromatography is carried out purifying with the 30% EtOAc wash-out that is in the hexanaphthene, obtains the title compound (12mg, 12%) of beige solid shape.
1H?NMR(400MHz,DMSO-d
6)δ9.88(s,1H),8.14-8.11(m,2H),7.99-7.88(m,3H),7.83(t,J=7.9Hz,1H),7.73(d,J=8.4Hz,1H),7.61-7.51(m,2H),7.46(d,J=7.3Hz,1H),6.80(d,J=5.0Hz,1H),2.41(s,3H)。(ESI+)m/z?370(M+H)
+。RT=2.88min (method 1).
The preparation of embodiment 019:2-bromo-6-(2-pyridin-3-yl-thiazole-5-yl)-pyridine
Under nonactive atmosphere; To at-78 ℃ of following refrigerative, be in 3-thiazol-2-yl-pyridine (J.Med.Chem., 2005,48 in the dry THF (30mL); 224) (927mg; 5.71mmol) in the solution that stirs, drip n-BuLi (2.5M is in the hexane) (2.75mL, 6.87mmol).-78 ℃ down stir 45min after, to wherein add tributyltin chloride (1.86mL, 6.87mmol).Make mixture in 90min, be warming up to 0 ℃, water is handled then, and extracts with ETHYLE ACETATE.Organic layer after merging is washed with salt solution, use MgSO
4Carry out drying, filter and vapourisation under reduced pressure, again through using combiflash
SiO
2Column chromatography is carried out purifying with cyclohexane/ethyl acetate from 100/0 to 82/18 wash-out, obtains 3-(5-tributyl stannyl-thiazol-2-yl)-pyridine (955mg, 37%) of colorless oil.
1H?NMR(DMSO-d
6,300MHz)δ=9.11(m,1H),8.62(dd,J=4.77-1.52Hz,1H),8.28(m,1H),7.90(s,1H),7.50(dd,J=8.0-4.8Hz,1H),1.52(m,6H),1.28(m,6H),1.13(m,6H),0.84(t,J=7.2Hz,9H)。
In ST, pack 2 into, the 6-dibromo pyridine (269mg, 1.13mmol), 3-(5-tributyl stannyl-thiazol-2-yl)-pyridine (511mg, 1.13mmol), Pd (PPh
3)
4(131mg, 0.11mmol), [1,1-two (diphenylphosphine) ferrocene] Palladous chloride (II) CH
2Cl
2(20mg is 0.024mmol) with through the dry toluene (5ml) of the degassing, and with being heated with stirring to 110 ℃ of following 36h.Cooled reaction mixture water is handled, and extracted with ETHYLE ACETATE.Organic layer after merging is used brine wash, use MgSO
4Carry out drying, filter and vapourisation under reduced pressure, again through using combiflash
SiO
2Column chromatography is carried out purifying with the cyclohexane/ethyl acetate wash-out, obtains the title compound (125mg, 35%) of white solid.
1HNMR(DMSO-d
6,300MHz)：δ=9.21(d,J=1.7Hz,1H),8.72(s,1H),8.70(m,1H),8.39(m,1H),8.14(d,J=7.8Hz,1H),7.88(dd,J=8.0；7.8Hz,1H),7.62(d,J=8.0Hz,1H),7.57(m,1H)。
Embodiment 020: the preparation of (4-methyl-pyridine-2-yl)-[6-(2-pyridin-3-yl-thiazole-5-yl)-pyridine-2-yl]-amine
In ST, pack into 2-bromo-6-(2-pyridin-3-yl thiazole-5-yl)-pyridine (125mg, 0.392mmol), 2-amino-4-picoline (51mg, 0.471mmol), Pd (OAc)
2(1.8mg, 8.01 μ mol), BINAP (7.4mg, 11.9 μ mol), Cs
2CO
3(255mg is 0.782mmol) with through the dry toluene (2ml) of the degassing, and along with being heated with stirring to 110 ℃ of following 48h.Cooled reaction mixture water is handled, and extracted with ETHYLE ACETATE.Organic layer after merging is washed with salt solution, use MgSO
4Carry out drying, filter and vapourisation under reduced pressure, again through using combiflash
SiO
2Column chromatography is carried out purifying with cyclohexane/ethyl acetate from 100/0 to 0/100 wash-out.Then, the solid that is obtained is ground in methyl alcohol, filter and drying, obtain the title compound of yellow solid shape.
1H?NMR(DMSO-d
6,300MHz)：δ=9.74(s,1H),9.15(d,J=2.1Hz,1H),8.68(m,1H),8.59(s,1H),8.31(m,1H),8.10(d,J=5.1Hz,1H),7.93(s,1H),7.72(dd,J=8.2-7.6Hz,1H),7.66-4.40(m,3H),6.77(d,J=4.9Hz,1H),2.37(s,3H)。(APCI+)m/z?346(M+H)
+。
The preparation of embodiment 021:2-bromo-6-(2-[1,3] dioxolane-2-base-thiazole-5-yl)-pyridine
In ST, pack 2 into, the 6-dibromo pyridine (525mg, 2.21mmol), 2-[1,3] dioxolane-2-base-5-tributyl stannyl-thiazole (J.Med.Chem., 2007,50,6303) (990mg, 2.21mmol), Pd (PPh
3)
4(256mg, 0.22mmol), [1,1-two (diphenylphosphine) ferrocene] Palladous chloride (II) CH
2Cl
2(30mg is 0.036mmol) with through the dry toluene (8ml) of the degassing, and along with being heated with stirring to 110 ℃ of following 48h.Cooled reaction mixture water is handled, and extracted with ETHYLE ACETATE.Organic layer after merging is washed with salt solution, use MgSO
4Carry out drying, filter and vapourisation under reduced pressure, again through using combiflash
SiO
2Column chromatography is carried out purifying with cyclohexane/ethyl acetate from 100/0 to 44/56 wash-out, obtains the title compound (370mg, 54%) of white solid.
1H?NMR(DMSO-d
6,300MHz)：δ=8.55(s,1H),8.06(dd,J=7.7-0.7Hz,1H),7.85(dd,J=7.9-7.7Hz,1H),7.61(dd,J=7.9-0.7Hz,1H),6.08(s,1H),4.15-4.00(m,4H)。
Embodiment 022: the preparation of [6-(2-[1,3] dioxolane-2-base-thiazole-5-yl)-pyridine-2-yl]-(4-methyl-pyridine-2-yl)-amine
In ST, pack into 2-bromo-6-(2-[1,3] dioxolane-2-base-thiazole-5-yl)-pyridine (350mg, 1.11mmol), 2-amino-4-picoline (145mg, 1.34mmol), Pd (OAc)
2(5mg, 22.2 μ mol), BINAP (21mg, 33.7 μ mol), Cs
2CO
3(728mg is 2.23mmol) with through the dry toluene (3ml) of the degassing, and along with being heated with stirring to 110 ℃ of following 24h.Cooled reaction mixture water is handled, and extracted with ETHYLE ACETATE.Organic layer after merging is washed with salt solution, use MgSO
4Carry out drying, filter and vapourisation under reduced pressure, again through using combiflash
SiO
2Column chromatography is carried out purifying with cyclohexane/ethyl acetate from 100/0 to 20/80 wash-out, obtains the title compound (276mg, 73%) of white solid.
1H?NMR(DMSO-d
6,300MHz)：δ=9.72(s,1H),8.44(s,1H),8.11(d,J=4.9Hz,1H),7.92(s,1H),7.72(dd,J=8.2-7.6Hz,1H),7.46(dd,J=8.9-7.6Hz,1H),6.78(d,J=4.9Hz,1H),6.08(s,1H),4.20-4.00(m,4H),2.34(s,3H)。
The preparation of embodiment 023:5-[6-(4-methyl-pyridine-2-base is amino)-pyridine-2-yl]-thiazole-2-formaldehyde
[6-(2-[1,3] dioxolane-2-base-thiazole-5-yl)-pyridine-2-yl]-(4-methyl-pyridine-2-yl)-amine in being in THF (8mL) (270mg, 0.793mmol) HCl (2mL) of adding 2N in the solution that stirs.With mixture 60 ℃ of following heated overnight.After the cooling, to wherein adding saturated NaHCO
3To alkaline pH, use the ethyl acetate extraction water then.Organic layer after merging is washed with salt solution, use MgSO
4Carry out drying, filter and vapourisation under reduced pressure, obtain the title compound (220mg, 94%) of yellow solid shape.
1H?NMR(DMSO-d
6,300MHz)：δ=9.94(s,1H),9.83(s,1H),8.87(s,1H),8.12(d,J=4.9Hz,1H),7.90(s,1H),7.78(m,1H),7.64(d,J=7.6Hz,1H),7.53(d,J=8.4Hz,1H),6.80(d,J=5.1Hz,1H),2.35(s,3H)。
The preparation of embodiment 024:E-(4-methyl-pyridine-2-yl)-[6-(2-styryl-thiazole-5-yl)-pyridine-2-yl]-amine
Under nonactive atmosphere, at 0 ℃ of following refrigerative, (176mg adds potassium tert.-butoxide (1.0M is among the THF) (675 μ L, 675 μ mol) in suspension-s 0.406mmol) to be in benzyl tri-phenyl-phosphorus bromide in the dry THF.Mixture is stirred 30min down at 0 ℃, add 5-[6-(4-methyl-pyridine-2-base is amino)-pyridine-2-yl]-thiazole-2-formaldehyde then once.After at room temperature stirring 3h, the reaction mixture water is handled, and extracted with ETHYLE ACETATE.Organic layer after merging is washed with salt solution, use MgSO
4Carry out drying, filter also evaporate to dryness under reduced pressure, again through using combiflash
SiO
2Column chromatography is carried out purifying with the cyclohexane/ethyl acetate wash-out.Then, make the E-isomer further carry out purifying with 5% methanol-eluted fractions that is in the methylene dichloride, obtain the title compound of yellow solid shape through the silica-gel plate preparative hplc.
1H NMR (acetone-d
6, 300MHz): δ=8.41 (s, 1H), 8.16 (d, J=5.1Hz, 1H), 8.00 (s, 1H), 7.80-7.70 (m, 3H), 7.65-7.55 (m, 2H), 7.53-7.36 (m, 4H), 7.50 (s, 1H), 6.84 (d, J=5.1Hz, 1H), 2.47 (s, 3H).(APCI+)m/z?371(M+H)
+。
The preparation of embodiment 049:6-(2-(4-p-methoxy-phenyl) thiazole-5-yl)-N-(4-picoline-2-yl) pyridine-2-amine
In ST, be in 2-bromo thiazole in the 20ml diox (0.54ml, 6.00mmol), (4-p-methoxy-phenyl) boric acid (1.00g, 6.60mmol) and K
2CO
3(2.50g, in the de-gassed solution 18.08mmol), the adding triphenylphosphine palladium (0.35mg, 0.29mmol).At N
2Reaction mixture is heated 16h down at 120 ℃ down.Reaction mixture is cooled off, and filter through
.Block is washed with DCM/EtOH, and filtrating is concentrated.2-(4-p-methoxy-phenyl) thiazole is carried out purifying (0.96g, 83%) through dried post flash chromatography with EtOAc/ hexanaphthene 10/90 wash-out.
1H?NMR(300MHz,DMSO-d
6)δ7.97(d,J=7.9Hz,2H),7.93(d,J=3.3,1H),7.77(d,J=3.3,1H),7.13(d,J=8.1Hz,2H),3.90(s,3H)。
Through according to preparation embodiment 019 identical in fact process, with 2-(4-p-methoxy-phenyl) thiazole (960mg, 5.01mmol) initial, obtain 2-(4-p-methoxy-phenyl)-5-(tributyl stannyl) thiazole, and pass through SiO
2Dried post flash chromatography carries out purifying (1.76g, 80%) with EtOAc/ hexanaphthene 10/90 wash-out.
1H?NMR(300MHz,DMSO-d
6)δ7.91(d,J=8.3Hz,2H),7.79(s,1H),7.07(d,J=8.5Hz,2H),3.84(s,3H),1.63-1.51(m,6H),1.40-1.25(m,6H),1.21-1.12(m,6H),0.89(t,J=7.3Hz,9H)。
In ST, pack 2 into, the 6-dibromo pyridine (474mg, 2.00mmol), 2-(4-p-methoxy-phenyl)-5-(tributyl stannyl) thiazole (920mg, 2.00mmol), Pd (PPh
3)
4(231mg, 0.20mmol) and through the degassing dry toluene (9ml), with it along with being heated with stirring to 120 ℃ of following 24h.Cooled reaction mixture water is handled, and extracted with ETHYLE ACETATE.Organic layer after merging is used MgSO
4Carry out drying, filter and vapourisation under reduced pressure, pass through SiO again
2Dried post flash chromatography carries out purifying with EtOAc/ hexanaphthene 20/80 wash-out, produces 5-(6-bromopyridine-2-yl)-2-(4-p-methoxy-phenyl) thiazole (410mg, 59%).
1H?NMR(300MHz,DMSO-d
6)δ8.55(s,1H),8.06(d,J=7.2Hz,1H),7.96(d,J=8.3Hz,2H),7.82(t,J=7.8Hz,1H),7.57(d,J=7.3Hz,1H),7.07(d,J=8.5Hz,2H),3.83(s,3H)。
Through according to the process identical in fact with embodiment 020; With 5-(6-bromopyridine-2-yl)-2-(4-p-methoxy-phenyl) thiazole (130mg; 0.37mmol) initial, obtain 6-(2-(4-p-methoxy-phenyl) thiazole-5-yl)-N-(4-picoline-2-yl) pyridine-2-amine, and pass through SiO
2Thin-layer chromatography is with EtOAc/MeOH (3%)-NEt
3(0.5%) wash-out carries out purifying (111mg, 80%).
1H?NMR(300MHz,DMSO-d
6)δ9.72(s,1H),8.48(s,1H),8.12(d,J=5.1Hz,1H),7.97(s,1H),7.94(d,J=8.8Hz,2H),7.72(t,J=7.9Hz,1H),7.48(d,J=7.4Hz,1H),7.44(d,J=8.3Hz,1H),7.11(d,J=8.8Hz,2H),6.80(d,J=5.2Hz,1H),3.85(s,3H),2.39(s,3H)。(APCI+)m/z?375(M+H)
+。
The preparation of embodiment 050:N-(3-(2-(4-p-methoxy-phenyl) thiazole-5-yl) phenyl)-4-picoline-2-amine
Through according to the process identical in fact with embodiment 019; With 1; The 3-dibromobenzene (0.250ml, 2.00mmol) and 2-(4-p-methoxy-phenyl)-5-(tributyl stannyl) thiazole (880mg, 2.00mmol) initial; Obtain 5-(3-bromophenyl)-2-(4-p-methoxy-phenyl) thiazole, and pass through SiO
2Dried post flash chromatography carries out purifying (406mg, 58%) with EtOAc/ hexanaphthene 20/80 wash-out.
1H?NMR(300MHz,DMSO-d
6)δ8.36(s,1H),7.96(t,J=1.8Hz,1H),7.92(d,J=8.9Hz,2H),7.72-7.67(m,1H),7.56(dd,J=4.9,4.0Hz,1H),7.42(t,J=7.9Hz,2H),7.10(d,J=8.9Hz,2H),3.84(s,3H)。
Through according to the process identical in fact with embodiment 020, with 5-(3-bromophenyl-2-(4-p-methoxy-phenyl) thiazole (and 130mg, 0.37mmol) initial, obtain N-(3-(2-(4-p-methoxy-phenyl) thiazole-5-yl) phenyl) 4-picoline-2-amine, and pass through SiO
2Thin-layer chromatography carries out purifying (26mg, 18%) with EtOAc/ hexanaphthene 50/50 wash-out.
1H?NMR(300MHz,DMSO)δ9.10(br?s,1H),8.15(s,1H),8.07(d,J=5.1Hz,1H),8.01(br?s,1H),7.92(d,J=8.6Hz,2H),7.71(d,J=7.5Hz,1H),7.33(t,J=7.8Hz,1H),7.22(d,J=6.9Hz,1H),7.08(d,J=8.7Hz,2H),6.70-6.61(m,2H),3.83(s,3H),2.25(s,3H)。(APCI+)m/z?374(M+H)
+。
The preparation of embodiment 051:4-(5-(6-(4-picoline-2-base is amino) pyridine-2-yl) thiazol-2-yl) cyanobenzene
2-bromo thiazole among the CH3CN in ST, that be in 75ml (0.63ml, 7.00mmol) with (4-cyano-phenyl) boric acid (1.00g, add in de-gassed solution 6.80mmol) triphenylphosphine palladium (0.35mg, 0.29mmol).To wherein adding Na
2CO
3The aqueous solution (0.4M, 35ml), at N
2Down reaction mixture is heated to 90 ℃ of following 24h.With the reaction mixture cooling, extract once with the water layer separation and with EtOAc (100ml).Organic phase after merging is used MgSO
4Carry out drying.After filtering and evaporating, 4-(thiazol-2-yl) cyanobenzene is carried out purifying (1.13g, 89%) through dried post flash chromatography with EtOAc/ hexanaphthene 20/80 wash-out.
1HNMR(300MHz,DMSO-d
6)δ8.14(d,J=8.3Hz,2H),8.03(d,J=3.2Hz,1H),8.00-7.93(m,3H)。
Through according to preparation embodiment 019 identical in fact process, with 4-(thiazol-2-yl) cyanobenzene (600mg, 3.22mmol) initial, obtain 4-(5-(tributyl stannyl) thiazol-2-yl) cyanobenzene, and pass through SiO
2Dried post flash chromatography carries out purifying (1.10g, 79%) with EtOAc/ hexanaphthene 10/90 wash-out.
1H?NMR(300MHz,DMSO-d
6)δ8.14(d,J=8.3Hz,2H),7.99-7.92(m,3H),1.62-1.47(m,6H),1.38-1.23(m,6H),1.21-1.14(m,6H),0.87(t,J=7.3Hz,9H)。
Through according to preparation embodiment 020 identical in fact process; With 6-bromo-N-(4-picoline-2-yl) pyridine-2-amine (100mg; 0.38mmol) and 4-(5-(tributyl stannyl) thiazol-2-yl) cyanobenzene (328mg; 0.69mmol) initial, obtain 4-(5-(6-(4-picoline-2-base is amino) pyridine-2-yl) thiazol-2-yl) cyanobenzene, and pass through SiO
2Dried post flash chromatography is with EtOAc/ hexanaphthene 50/50-MeOH (5%) wash-out and through using Et
2O grinds and carries out purifying (51mg, 37%).
1H?NMR(300MHz,DMSO-d
6)δ9.77(br?s,1H),8.65(s,1H),8.20-8.10(m,3H),8.00(d,J=8.4Hz,2H),7.93(br?s,1H),7.75(t,J=7.9Hz,1H),7.55(d,J=7.4Hz,1H),7.50(d,J=8.3Hz,1H),6.80(d,J=5.1Hz,1H),2.39(s,3H).(APCI+)m/z?370(M+H)
+。
The preparation of embodiment 052:4-(5-(6-(4-picoline-2-base is amino) pyridine-2-yl) thiazol-2-yl) BM
(embodiment 051, and 40mg 0.11mmol) is suspended among the EtOH (8ml) for cyanobenzene with 4-(5-(6-(4-picoline-2-base is amino) pyridine-2-yl) thiazol-2-yl).To wherein successively add ammoniacal liquor (28%-30%, 4ml) and H
2O
2(35%, 1ml).Reaction mixture was stirred 2.5 days down at 40 ℃.To wherein adding ammoniacal liquor (2ml) and H
2O
2(0.250ml), and with reaction mixture further stir 24h down at 40 ℃.Make and be reflected at H
2Distribute among O (30ml) and the EtOAc (70ml).After the separation, use EtOAc (70ml) to extract once more water.In evaporation and pass through SiO
2Dried post flash chromatography is with EtOAc/MeOH (5%-10%)/NEt
3(0.5%) after wash-out carries out purifying, obtains 4-(5-(6-(4-picoline-2-base the is amino) pyridine-2-yl) thiazol-2-yl) BM (46mg, 74%) of yellow solid shape.
1H?NMR(300MHz,DMSO-d
6)δ9.72(br?s,1H),8.59(br?s,1H),8.20-7.98(m,6H),7.95(d,J=8.6Hz,1H),7.78-7.70(m,1H),7.66(d,J=8.8Hz,1H),7.57-7.45(m,3H),2.25(s,3H)。(APCI+)m/z?388(M+H)
+。
The preparation of embodiment 053:6-(2-(4-p-methoxy-phenyl) thiazole-5-yl)-N-(5-picoline-2-yl) pyridine-2-amine
Through according to preparation embodiment 050 identical in fact process; With 5-(6-bromopyridine-2-yl)-2-(4-p-methoxy-phenyl) thiazole (100mg; 0.29mmol) initial, obtain 6-(2-(4 p-methoxy-phenyl) thiazole-5-yl)-N-(5-picoline-2-yl) pyridine-2-amine, and pass through at Et
2Grind purifying (66mg, 61%) among the O/DCM.
1H?NMR(300MHz,DMSO-d
6)δ9.67(s,1H),8.09(d,J=2.3Hz,1H),7.98-7.91(m,3H),7.71(t,J=7.9Hz,1H),7.63(dd,J=8.5,2.4Hz,1H),7.45(d,J=7.9Hz,1H),7.09(d,J=8.3Hz,1H),3.85(s,3H),2.25(s,3H)。(APCI+)m/z?374(M+H)
+。RT=2.66min (method 2).
The preparation of embodiment 054:3-(5-(6-(4-methylpyrimidine-2-base is amino) pyridine-2-yl) thiazol-2-yl) cyanobenzene
Under nonactive atmosphere, the NaH in being in THF (15ml) (60%, be in the oil, 1g, 25.32mmol) drip in the cooled suspending liquid 2-amino-4-methylpyrimidine be among the THF (10ml) (980mg, 8.86mmol).Reaction mixture is heated 2h down at 55 ℃.With reaction cooled to 0 ℃, and be in 2 among the THF (20ml), 6-dibromo pyridine (2g, solution 8.44mmol) to wherein adding.Reaction mixture is heated 5h down at 80 ℃.Make reaction cooled to 0 ℃, and water (50ml) is hydrolyzed carefully.(after 2 * 100ml) extractions, the extract after merging is used MgSO with EtOAc
4Carry out drying.After filtering and evaporating, obtain N-(6-bromopyridine-2-yl)-4-methylpyrimidine-2-amine, and pass through SiO
2Dried post flash chromatography is with DCM/MeOH (1%)/NEt
3(0.5%) wash-out carries out purifying (0.846g, 38%).
1H?NMR(300MHz,DMSO-d
6)δ10.12(br?s,1H),8.44(d,J=5.0Hz,1H),8.36(d,J=8.3Hz,1H),7.69(t,J=8.0Hz,1H),7.18(dd,J=7.6,0.6Hz,1H),6.91(d,J=5.0Hz,1H),2.42(s,3H)。
Through according to preparation embodiment 019 identical in fact process; With N-(6-bromopyridine-2-yl)-4-methylpyrimidine-2-amine (215mg; 0.81mmol) and 3-(5-(tributyl stannyl) thiazol-2-yl) cyanobenzene (656mg; 1.38mmol) initial, obtain 3-(5-(6-(4-methylpyrimidine-2-base is amino) pyridine-2-yl) thiazol-2-yl) cyanobenzene, and pass through SiO
2Dried post flash chromatography is with DCM/MeOH (5%)/NEt
3(0.5%) wash-out, in DCM/MeOH deposition, use Et again
2O grinds and carries out purifying (119mg, 39%).
1H?NMR(300MHz,DMSO-d
6)δ9.60(br?s,1H),8.62(s,1H),8.43(d,J=5.0Hz,1H),8.38(d,J=2.3Hz,1H),8.31-8.23(m,2H),8.01-7.95(m,1H),7.86(t,J=8.0Hz,1H),7.75(t,J=7.9Hz,1H),7.64(d,J=7.5Hz,1H),6.89(d,J=5.0Hz,1H),2.42(s,3H)。(APCI+)m/z?371(M+H)
+。
Through using suitable parent material and condition to repeat method mentioned above, be able in the his-and-hers watches 1 following other analogue and prepare and characterize.
Table 1
The embodiment of external protein kinase inhibition test
Process
Flt-3WT and sudden change Flt-3 test
Clone
Ba/F3 people Flt-3WT (wild-type) and Flt-3 ITD (internal series-connection repetition) clone is derived from mouse IL-3 dependency Ba/F3proB lymphocyte.Ba/F3 people Flt-3WT cell is able to growth under the situation that IL3 exists, and the growth of the Ba/F3 cell of the expressing human Flt-3 ITD dependent cells factor not.The formerly existing description (Cast é ran etc., Cell.Mol.Biol., 40, pp.443-456,1994) that said clone and people Flt-3 construct are carried out.MV4-11 is the human leukemia cell line, and it is derived from the patient who suffers from the AML that expresses mutant form Flt-3ITD.
Propagation and viability test based on cell
All clone has all been carried out cell survival/proliferation test (from the CellTiter-Blue cell viability test of Promega ref.G8081).
Altogether with 2 * 10
4Cells/well/50 μ l are inoculated in 96 orifice plates.Through to wherein add 2 * the medicament solution from 1/2 serial dilution of 0 μ M to 10 μ M, begin to handle.Make cell at 37 ℃ of 48h that grow down, under 37 ℃, hatch 4h then with the CellTiter-Blue reagent in 10 μ l/ holes.Said test is based on through being converted into resorufin at activatory cell aspect the metabolism with resazurin, thereby generates fluorescence-causing substance.Use scanning porous spectrophotometer (POLARstar Omega, BMG labtech, France), excite at 544nm place and after the 590nm place launches, fluorescence is measured.Acellular blank well is contrasted as background, and all tests all repeat at least twice with three parallel laboratory tests.The result is expressed as the per-cent that accounts for the proliferation function that obtains when not carrying out handling (DMSO contrast).All medicines are all processed the 20mM stock solution that is among the DMSO, and preserve down in-80 ℃.Before each experiment, in substratum, process fresh diluent.
Exempt to survey precipitation test and western engram analysis
For each test, table 1 compound of concentration is to 5 * 10 shown in using
6Ba/F3 Flt-3 ITD or MV4-11 cell were handled 1 hour 30 minutes.According to Beslu etc., J.Biol.Chem., 271, pp.20075-20081,1996 is said, with cell harvesting, cracking and carry out immunoprecipitation.Make cell lysate with rabbit immune serum (Santa Cruz SC-480) immunoprecipitation to Flt-3.With the hybridization of western trace thing and the anti-phosphotyrosine antibody of 4G10 (UBI) or with anti-Flt-3 rabbit immune serum hybridization.Then, the goat anti-mouse IgG antibody of film and HRP being puted together or hatch with the goat anti-rabbit igg antibody (Immunotech) that HRP puts together.Next, through hatching, make institute's protein of interest visible with ECL reagent (Amersham).
The Syk test
SYK kinases purifying is the full-length proteins in the rhabdovirus system of approximate homogeneous.JAKs kinases (JAK1, JAK2 and JAK3) is available from Invitrogen or Millipore.All kinase assay are carried out in Kinease TK (casein kinase) HTRF (homogeneous phase time discrimination fluorescence) test with Cisbio international exploitation.These tests at room temperature, in the white culture plate in 96 Kong Ban districts, at kinase buffer liquid (the 10mM MgCl of 25 μ l final volume
22mM MnCl
250mM HEPES sodium pH7.8; BRIJ-35,0.01%, 1 μ M substrate) carry out in (contain concentration and double the ATP of each enzyme Km and an amount of recombinase at least), thus guarantee linear response speed.Be reflected at when introducing enzyme initial, along with the HTRF that adds a reaction volume (25 μ l) detects damping fluid and stops.Culture plate was at room temperature hatched 1 hour, and Measuring Time is differentiated the FRET signal in Pherastar FS ELIASA (BMG Labtech).
All data are the MV of three parallel laboratory tests, standard deviation < 10%.
Experimental result
In table 2, listed the experimental result of the various The compounds of this invention that use above-mentioned experimental program.
Table 2: each compound is to the vitro inhibition effect of Flt-3WT, Flt-3ITD and/or Syk.
IC50: the concentration that 50% protein kinase acceptor of target cell is suppressed.
Experiment and result's explanation
The inventor has observed formula I compounds of the present invention to protein kinase, especially Tyrosylprotein kinase, the extremely effective restraining effect of Flt-3 and/or Flt-3ITD and/or syk more particularly.The compound that table 2 is listed has been represented this type formula I compound well.
Claims (23)
1. the compound of a formula I:
Formula I
Wherein, substituent A, Q, X, the R among the formula I
1, R
2, R
3, V and W be as giving a definition:
A is one of following group:
I) N (R
4) (CH
2)
n, wherein, 0<n<3;
Ii) O (CH
2)
n, wherein, 0<n<3;
Iii) S (CH
2)
n, wherein, 0<n<3;
Iv) (CH
2)
n, wherein, 0≤n<4;
V) C (O) (CH
2)
n, wherein, 0<n<3;
vi）C(R
4)=C(R
5)；
vii）C≡C(R
5)；
R
4And R
5Be hydrogen, C independently of one another
1-4Alkyl, C
2-6Thiazolinyl, C
2-6Alkynyl, C
3-7Naphthenic base, C
1-4Haloalkyl, C
1-4Alkoxyl group, C
1-4Hydroxyalkyl, C
1-4Alkylamino;
X is CH or N;
V is O or S;
Q is selected from:
I) alkyl
1Group, or
Ii) aryl
1Group, or
Iii) heteroaryl
1Group;
With alkyl
1Group definition is straight chain, side chain or the group of naphthene base that comprises 1-10 carbon atom, and optional replaces with following radicals: one or more heteroatomss, like halogen (being selected from F, Cl, Br or I), oxygen and nitrogen; And trifluoromethyl, carboxyl, cyanic acid, nitro, formyl radical; And CO-R, COO-R, CONR-R ', SO
2-R and SO
2NR-R ', wherein, R and R ' they are the straight or branched alkyl group that comprises 1-10 carbon atom, and optional with at least one heteroatoms, particularly halogen (being selected from F, Cl, Br or I), oxygen and nitrogen replacement; And naphthenic base or aryl
1Group or heteroaryl
1Group;
With aryl
1Group definition be phenyl or the ring arbitrary position on have one or more substituent arbitrary combination the substituted-phenyl variant, said substituting group for example:
-halogen (being selected from I, F, Cl or Br);
-alkyl
1Group;
-group of naphthene base, aromatic yl group or heteroaryl groups;
-trifluoromethyl, O-alkyl, carboxyl, cyanic acid, nitro, formyl radical, hydroxyl, NH-alkyl, N (alkyl) (alkyl) and amino group;
-NRCO-R ' or NRCOO-R ' or NRCONR '-R " or NRSO
2-R ' or NRSO
2NR '-R " or CO-R or COO-R or CONR-R ' or SO
2-R or SO
2NRR ', wherein, R, R ' and R " are selected from hydrogen, alkyl, aryl or heteroaryl groups independently of one another;
With heteroaryl
1Group definition be for can having the pyridyl, pyrimidyl, pyrazinyl, pyridazinyl, thienyl, thiazolyl, imidazolyl, pyrazolyl, pyrryl, furyl 、 oxazolyl 、 isoxazolyl, triazolyl, tetrazyl, indyl, benzoglyoxaline, benzoxazole, benzothiazole, quinolyl group etc. of one or more substituent arbitrary combination in addition on arbitrary position of ring, said substituting group as:
-halogen (being selected from F, Cl, Br or I);
-alkyl
1Group;
-naphthenic base, aryl or heteroaryl groups;
-trifluoromethyl, O-alkyl, carboxyl, cyanic acid, nitro, formyl radical, hydroxyl, NH-alkyl, N (alkyl) (alkyl) and amino group;
-NRCO-R ' or NRCOO-R ' or NRCONR '-R " or NRSO
2-R ' or NRSO
2NR '-R " or CO-R or COO-R or CONR-R ' or SO
2-R or SO
2NRR ', wherein, R, R ' and R " are selected from hydrogen, alkyl, aryl or heteroaryl groups independently of one another;
R
1, R
2And R
3Be selected from hydrogen, halogen (being selected from F, Cl, Br or I) independently of one another, comprise the straight or branched alkyl of 1-10 carbon atom; Said straight or branched alkyl is optional to be replaced with following group: one or more heteroatomss, like halogen (being selected from F, Cl, Br or I), oxygen and nitrogen; And trifluoromethyl, C
1-6Alkoxyl group, amino, C
1-6Alkylamino, two (C
1-6Alkyl) amino, carboxyl, cyanic acid, nitro, formyl radical, hydroxyl, CO-R, COO-R, CONR-R ', SO
2-R and SO
2NR-R ', wherein, R and R ' are corresponding to hydrogen, alkyl, aryl or heteroaryl groups;
W is an aryl
1Or heteroaryl
1
2. according to the compound described in the claim 1, said compound has formula II:
Formula II
Wherein, R
1, R
2, R
3, X, V and W have the implication described in claim 1; And
Wherein, R
6, R
7, R
8, R
9And R
10Be selected from hydrogen, halogen (being selected from F, Cl, Br or I) independently of one another, comprise the straight or branched alkyl group of 1-10 carbon atom; Said straight or branched alkyl group is optional to be replaced with following group: one or more heteroatomss, like halogen (being selected from F, Cl, Br or I), oxygen and nitrogen; And trifluoromethyl, C
1-6Alkoxyl group, amino, C
1-6Alkylamino, two (C
1-6Alkyl) amino, carboxyl, cyanic acid, nitro, formyl radical, hydroxyl, CO-R, COO-R, CONR-R ', SO
2-R and SO
2NR-R ', wherein, R and R ' are selected from hydrogen, alkyl, aryl or heteroaryl groups independently of one another.
3. according to the compound described in the claim 1, said compound has formula III:
Formula III
Wherein, Z is an aryl
1Or heteroaryl
1R
1, R
2, R
3, X, V, W, aryl
1And heteroaryl
1Has the implication described in claim 1.
4. according to the compound described in the claim 1, said compound has formula Ia:
Formula Ia
Wherein, A, Q, R
1, R
2, R
3With V in the claim 1-3 definition, and W
1Be selected from hydrogen, halogen (being selected from F, Cl, Br or I), comprise one or more in the straight or branched alkyl group of 1-10 carbon atom; Said straight or branched alkyl group is optional to be replaced with following group: one or more heteroatomss, like halogen (being selected from F, Cl, Br or I), oxygen and nitrogen; And trifluoromethyl, C
1-6Alkoxyl group, amino, C
1-6Alkylamino, two (C
1-6Alkyl) amino, carboxyl, cyanic acid, nitro, formyl radical, hydroxyl, CO-R, COO-R, CONR-R ', SO
2-R and SO
2NR-R ', wherein, R and R ' are selected from hydrogen, alkyl, aryl or heteroaryl groups independently of one another.
5. according to the compound described in the claim 1, said compound is represented by Formula Il a:
Formula IIa
Wherein, R
1, R
2, R
3, R
6, R
7, R
8, R
9And R
10, V and W1 have the implication described in claim 1-4.
6. according to the compound described in the claim 1, said compound is represented by Formula Il Ia:
Formula III a
Wherein, R
1, R
2, R
3, V, W1 and Z have the implication described in claim 1-4.
7. compound as claimed in claim 1, said compound is selected from:
(4-methyl-pyridine-2-yl)-[6-(2-styroyl-oxazoles-5-yl)-pyridine-2-yl]-amine;
(4-methyl-pyridine-2-yl)-[3-(2-phenyl sulfenyl-oxazoles-5-yl)-phenyl]-amine;
(3-{2-[2-(4-methoxyl group-phenyl)-vinyl]-oxazoles-5-yl }-phenyl)-(4-methyl-pyridine-2-yl)-amine;
(6-{2-[2-(4-methoxyl group-phenyl)-vinyl]-oxazoles-5-yl }-pyridine-2-yl)-(4-methyl-pyridine-2-yl)-amine;
(4-methyl-pyridine-2-yl)-[6-(2-styryl-oxazoles-5-yl)-pyridine-2-yl]-amine;
Pyridine-2-base-[6-(2-styryl-oxazoles-5-yl)-pyridine-2-yl]-amine;
(6-{2-[2-(4-methoxyl group-phenyl)-vinyl]-oxazoles-5-yl }-pyridine-2-yl)-pyridine-2-base-amine;
(6-{2-[2,6-dimethyl--4-(2-morpholine-4-base-oxyethyl group)-phenyl]-oxazoles-5-yl }-pyridine-2-yl)-(4-methyl-pyridine-2-yl)-amine;
(5-chloro-pyridine-2-yl)-[6-(2-phenyl-oxazoles-5-yl)-pyridine-2-yl]-amine;
(4-methyl-piperazine-1-yl)-(3-{5-[3-(4-methyl-pyridine-2-base is amino)-phenyl]-oxazoles-2-yl }-phenyl)-ketone;
3-(4-methyl-pyridine-2-base is amino)-5-(2-thiene-3-yl--oxazoles-5-yl)-cyanobenzene;
4-{5-[6-(5-methyl-pyridine-2-base is amino)-pyridine-2-yl]-thiazol-2-yl }-cyanobenzene;
{ 6-[2-(4-methoxyl group-phenyl)-thiazole-5-yl]-pyridine-2-yl }-(6-methyl-pyridine-2-yl)-amine;
(4-methyl-pyridine-2-yl)-{ 3-[2-(3-trifluoromethyl-phenyl)-oxazoles-5-yl]-phenyl }-amine;
4-(2-{5-[6-(4-methyl-pyridine-2-base is amino)-pyridine-2-yl]-oxazoles-2-yl }-vinyl)-cyanobenzene;
4-(2-{5-[6-(4-methyl-pyridine-2-base is amino)-pyridine-2-yl]-oxazoles-2-yl }-ethyl)-cyanobenzene;
(4-methyl-pyridine-2-yl)-[6-(2-pyridin-3-yl-oxazoles-5-yl)-pyridine-2-yl]-amine;
N-(2-hydroxyl-ethyl)-N-methyl-3-{5-[6-(4-methyl-pyridine-2-base is amino)-pyridine-2-yl]-oxazoles-2-yl }-benzsulfamide;
(4-methyl-pyridine-2-yl)-{ 6-[2-(3-tetramethyleneimine-1-ylmethyl-phenyl)-oxazoles-5-yl]-pyridine-2-yl }-amine hydrochlorate;
(4-methyl-pyridine-2-yl)-{ 6-[2-(3-morpholine-4-ylmethyl-phenyl)-oxazoles-5-yl]-pyridine-2-yl }-amine hydrochlorate;
(5-chloro-pyridine-2-yl)-[6-(2-thiene-3-yl--oxazoles-5-yl)-pyridine-2-yl]-amine;
{ 6-[2-(1H-indoles-5-yl)-oxazoles-5-yl]-pyridine-2-yl }-pyrazine-2-base-amine;
{ 6-[2-(1H-indoles-5-yl)-oxazoles-5-yl]-5-methyl-pyridine-2-yl }-(4-methyl-pyridine-2-yl)-amine;
[6-(2-cyclohexyl sulfenyl-oxazoles-5-yl)-pyridine-2-yl]-(4-methyl-pyridine-2-yl)-amine;
5-[6-(4-picoline-2-base is amino) pyridine-2-yl]-N-(pyridin-4-yl methyl) oxazole-2-amine;
N-(4-methoxy-benzyl)-5-[6-(4-picoline-2-base is amino) pyridine-2-base] oxazole-2-amine;
4-{5-[6-(4-picoline-2-base is amino) pyridine-2-yl]-oxazoles-2-yl }-piperazine-2-ketone
{ 6-[2-(4-methyl-piperazine-1-yl)-oxazoles-5-yl]-pyridine-2-yl }-(3-trifluoromethyl-phenyl)-amine;
(6-{2-[4-(2-methoxy ethyl)-piperazine-1-yl]-oxazoles-5-yl }-pyridine-2-yl)-(4-methyl-pyridine-2-yl)-amine;
1-(2-methoxyl group-ethyl)-4-{5-[3-(4-methyl-pyrimidine-2--amino)-phenyl]-oxazoles-2-yl }-piperazine-2-ketone;
3-{2-[(2-methoxyl group-ethyl)-methyl-amino]-oxazoles-5-yl }-5-(4-methyl-pyridine-2-base is amino)-cyanobenzene;
(4-methyl-pyridine-2-yl)-[6-(2-pyridine-2-base-oxazoles-5-yl)-pyridine-2-yl]-amine;
(4-methyl-pyridine-2-yl)-[6-(2-phenyl-oxazoles-5-yl)-pyridine-2-yl]-amine;
(4-methyl-pyridine-2-yl)-(3-{2-[2-(3-trifluoromethyl-phenyl)-vinyl]-oxazoles-5-yl }-phenyl)-amine;
{ 6-[2-(2-methoxyl group-pyridin-3-yl)-oxazoles-5-yl]-pyridine-2-yl }-(4-methyl-pyridine-2-yl)-amine;
3-{5-[6-(4-methyl-pyridine-2-base is amino)-pyridine-2-yl]-oxazoles-2-yl }-the 1H-pyridin-2-ones;
3-{5-[6-(4-methyl-pyridine-2-base is amino)-pyridine-2-yl]-oxazoles-2-yl }-1-(2-morpholine-4-base-ethyl)-1H-pyridin-2-ones;
(4-methyl-pyridine-2-yl)-[6-(2-phenylacetylene base-oxazoles-5-yl)-pyridine-2-yl]-amine;
[6-(2-benzoxazole-2-base-oxazoles-5-yl)-pyridine-2-yl]-(4-methyl-pyridine-2-yl)-amine;
(4-methyl-pyridine-2-yl)-[6-(2-pyridin-3-yl-thiazole-5-yl)-pyridine-2-yl]-amine;
E-(4-methyl-pyridine-2-yl)-[6-(2-styryl-thiazole-5-yl)-pyridine-2-yl]-amine;
6-(2-(4-p-methoxy-phenyl) thiazole-5-yl)-N-(4-picoline-2-yl) pyridine-2-amine;
N-(3-(2-(4-p-methoxy-phenyl) thiazole-5-yl) phenyl)-4-picoline-2-amine;
4-(5-(6-(4-picoline-2-base is amino) pyridine-2-yl) thiazol-2-yl) cyanobenzene;
4-(5-(6-(4-picoline-2-base is amino) pyridine-2-yl) thiazol-2-yl) BM;
6-(2-(4-p-methoxy-phenyl) thiazole-5-yl)-N-(5-picoline-2-yl) pyridine-2-amine;
3-(5-(6-(4-methylpyrimidine-2-base is amino) pyridine-2-yl) thiazol-2-yl) cyanobenzene;
(4-methyl-pyridine-2-yl)-[6-{2-[3-(2-morpholine-4-base-oxyethyl group)-phenyl]-oxazoles-5-yl }-pyridine-2-yl]-amine;
(4-methyl-pyridine-2-yl)-[6-(2-phenyl-thiazole-5-yl)-pyridine-2-yl]-amine;
(4-methyl-pyridine-2-yl)-[6-{2-[3-(2-morpholine-4-base-oxyethyl group)-phenyl]-oxazoles-5-yl }-pyridine-2-yl]-amine;
(4-methyl-pyridine-2-yl)-(6-{2-[2-(2-morpholine-4-base-oxyethyl group)-phenyl]-oxazoles-5-yl }-pyridine-2-yl)-amine;
{ 6-[2-(2-methoxyl group-phenyl)-oxazoles-5-yl]-pyridine-2-yl }-(4-methyl-pyridine-2-yl)-amine;
{ 6-[2-(2,4-dimethoxy-phenyl)-thiazole-5-yl]-pyridine-2-yl }-(4-methyl-pyridine-2-yl)-amine;
(4-methyl-pyridine-2-yl)-[6-(2-o-tolyl-oxazoles-5-yl)-pyridine-2-yl]-amine;
{ 6-[2-(2,6-dimethyl--phenyl)-oxazoles-5-yl]-pyridine-2-yl }-(4-methyl-pyridine-2-yl)-amine;
4-{5-[6-(4-methyl-pyridine-2-base is amino)-pyridine-2-yl]-oxazoles-2-yl }-cyanobenzene;
3-{5-[6-(4-methyl-pyridine-2-base is amino)-pyridine-2-yl]-thiazol-2-yl }-cyanobenzene;
(4-methyl-pyridine-2-yl)-{ 6-[2-(3-trifluoromethyl-phenyl)-oxazoles-5-yl]-pyridine-2-yl }-amine;
(4-methyl-pyridine-2-yl)-{ 6-[2-(4-trifluoromethyl-phenyl)-oxazoles-5-yl]-pyridine-2-yl }-amine;
(4-methyl-piperazine-1-yl)-(3-{5-[6-(4-methyl-pyridine-2-base is amino)-pyridine-2-yl]-oxazoles-2-yl }-phenyl)-ketone;
3-{5-[6-(4-methyl-pyridine-2-base is amino)-pyridine-2-yl]-thiazol-2-yl }-BM;
{ 6-[2-(1H-indoles-5-yl)-oxazoles-5-yl]-pyridine-2-yl }-(4-methyl-pyridine-2-yl)-amine;
[6-(2-furans-2-base-oxazoles-5-yl)-pyridine-2-yl]-(4-methyl-pyridine-2-yl)-amine;
4-{5-[6-(3-trifluoromethyl-phenyl amino)-pyridine-2-yl]-oxazoles-2-yl }-piperazine-2-ketone;
{ 5-methyl-6-[2-(4-methyl-piperazine-1-yl)-oxazoles-5-yl]-pyridine-2-yl }-(4-methyl-pyridine-2-yl)-amine;
4-{5-[3-methyl-6-(4-methyl-pyridine-2-base is amino)-pyridine-2-yl]-oxazoles-2-yl }-piperazine-2-ketone;
(4-methyl-pyridine-2-yl)-[5-methyl-6-(2-thiene-3-yl--oxazoles-5-yl)-pyridine-2-yl]-amine;
1-(2-methoxyl group-ethyl)-4-{5-[3-methyl-6-(4-methyl-pyridine-2-base is amino)-pyridine-2-yl]-oxazoles-2-yl }-piperazine-2-ketone;
4-{5-[3-fluoro-6-(4-methyl-pyridine-2-base is amino)-pyridine-2-yl]-oxazoles-2-yl }-1-(2-methoxyl group-ethyl)-piperazine-2-ketone;
4-{5-[3-fluoro-6-(4-methyl-pyridine-2-base is amino)-pyridine-2-yl]-oxazoles-2-yl }-piperazine-2-ketone;
(5-fluoro-6-{2-[4-(4-methyl-piperazine-1-yl)-phenyl]-oxazoles-5-yl }-pyridine-2-yl)-(4-methyl-pyridine-2-yl)-amine;
1-{5-[6-(pyridine-2-base is amino)-pyridine-2-yl]-oxazoles-2-yl }-piperidines-4-carboxylic acid amide;
(4-methyl-pyridine-2-yl)-[6-(2-pyridine-2-base-thiazole-5-yl)-pyridine-2-yl]-amine;
(4-methyl-pyridine-2-yl)-[6-(2-thiophene-2-base-oxazoles-5-yl)-pyridine-2-yl]-amine;
[6-(2-benzo [b]-thiophene-2-base-thiazole-5-yl)-pyridine-2-yl]-(4-methyl-pyridine-2-yl)-amine;
(4-methyl-pyridine-2-yl)-[6-(2-thiene-3-yl--oxazoles-5-yl)-pyridine-2-yl]-amine;
{ 6-[2-(2-methoxyl group-4-methyl-pyridin-3-yl)-oxazoles-5-yl]-pyridine-2-yl }-(4-methyl-pyridine-2-yl)-amine;
{ 6-[2-(6-methoxyl group-pyridin-3-yl)-oxazoles-5-yl]-pyridine-2-yl }-(4-methyl-pyridine-2-yl)-amine;
{ 6-[2-(2,4-dimethoxy-phenyl)-thiazole-5-yl]-pyridine-2-yl }-(5-methyl-pyridine-2-yl)-amine;
3-{5-[6-(5-methyl-pyridine-2-base is amino)-pyridine-2-yl]-thiazol-2-yl }-cyanobenzene;
5-{5-[6-(4-methyl-pyridine-2-base is amino)-pyridine-2-yl]-oxazoles-2-yl }-the 1H-pyridin-2-ones;
3-{5-[6-(4-methyl-pyridine-2-base is amino)-pyridine-2-yl]-oxazoles-2-yl }-1-(2-tetramethyleneimine-1-base-ethyl)-1H-pyridin-2-ones;
5-{5-[6-(4-methyl-pyridine-2-base is amino)-pyridine-2-yl]-oxazoles-2-yl }-1-(2-morpholine-4-base-ethyl)-1H-pyridin-2-ones;
[6-(2-cumarone-2-base-oxazoles-5-yl)-pyridine-2-yl]-(4-methyl-pyridine-2-yl)-amine;
3-{5-[6-(5-methyl-pyridine-2-base is amino)-pyridine-2-yl]-thiazol-2-yl }-BM;
(4-methyl-pyridine-2-yl)-(6-{2-[2-(4-trifluoromethoxy-phenyl)-vinyl]-oxazoles-5-yl }-pyridine-2-yl)-amine;
{ 6-[2-(4-methoxyl group-phenylacetylene base)-oxazoles-5-yl]-pyridine-2-yl }-(4-methyl-pyridine-2-yl)-amine;
4-{5-[6-(4-methyl-pyridine-2-base is amino)-pyridine-2-yl]-oxazoles-2-ethyl-acetylene base }-cyanobenzene;
(5-methyl-pyridine-2-yl)-[6-(2-pyridine-2-base-thiazole-5-yl)-pyridine-2-yl]-amine;
(4-methyl-pyridine-2-yl)-[6-(2-tetramethyleneimine-1-base-oxazoles-5-yl)-pyridine-2-yl]-amine;
(4-methyl-pyridine-2-yl)-[6-(2-piperidines-1-base-oxazoles-5-yl)-pyridine-2-yl]-amine;
(4-methyl-pyridine-2-yl)-[6-(2-morpholine-4-base-oxazoles-5-yl)-pyridine-2-yl]-amine;
4-{5-[6-(4-methylpyrimidine-2-base is amino)-pyridine-2-yl]-thiazol-2-yl }-cyanobenzene;
4-{5-[6-(4-methyl-pyridine-2-base is amino)-pyridine-2-yl]-oxazoles-2-yl }-piperazine-2-ketone;
(4-methyl-pyridine-2-yl)-[6-(2-thiomorpholine-4-base-oxazoles-5-yl)-pyridine-2-yl]-amine;
{ 6-[2-(4-methyl-piperazine-1-yl)-oxazoles-5-yl]-pyridine-2-yl }-(4-methyl-pyridine-2-yl)-amine;
(4-methyl-pyrimidine-2-base)-[6-(2-pyridine-2-base-thiazole-5-yl)-pyridine-2-yl]-amine;
1-{5-[6-(4-methyl-pyridine-2-base is amino)-pyridine-2-yl]-oxazoles-2-yl }-piperidines-4-carboxylic acid amide;
(4-methyl-pyridine-2-yl)-6-[2-(the amino) oxazole of 2-methoxy ethyl-5-yl])-pyridine-2-yl }-amine;
(4-methyl-pyridine-2-yl)-6-[2-(2-morpholinyl-4-base-ethyl)-amino-oxazoles-5-yl])-pyridine-2-yl }-amine;
1-(2-methoxy ethyl)-4-{5-[6-(4-methyl-pyridine-2-base is amino)-pyridine-2-yl]-oxazoles-2-yl }-piperazine-2-ketone;
3-{5-[6-(4-methyl-pyrimidine-2--amino)-pyridine-2-yl]-thiazol-2-yl }-BM;
[6-(2-cyclopentyl-sulfenyl-oxazoles-5-yl)-pyridine-2-yl]-(4-methyl-pyridine-2-yl)-amine;
(3-methyl-pyridine-2-yl)-[6-(2-phenyl-oxazoles-5-yl)-pyridine-2-yl]-amine;
{ 6-[2-(1H-indoles-5-yl)-oxazoles-5-yl]-pyridine-2-yl }-(3-methyl-pyridine-2-yl)-amine;
(3-methyl-pyridine-2-yl)-[6-(2-thiene-3-yl--oxazoles-5-yl)-pyridine-2-yl]-amine;
(5-methyl-pyridine-2-yl)-[6-(2-phenyl-oxazoles-5-yl)-pyridine-2-yl]-amine;
(5-methyl-pyridine-2-yl)-[6-(2-thiene-3-yl--oxazoles-5-yl)-pyridine-2-yl]-amine;
{ 6-[2-(1H-indoles-5-yl)-oxazoles-5-yl]-pyridine-2-yl }-(5-methyl-pyridine-2-yl)-amine;
(5-methyl-pyridine-2-yl)-[6-(2-tetramethyleneimine-1-base-oxazoles-5-yl)-pyridine-2-yl]-amine;
4-{5-[6-(5-methyl-pyridine-2-base is amino)-pyridine-2-yl]-oxazoles-2-yl }-piperazine-2-ketone;
{ 6-[2-(4-methyl-piperazine-1-yl)-oxazoles-5-yl]-pyridine-2-yl }-(5-methyl-pyridine-2-yl)-amine;
(4-chloro-pyridine-2-yl)-[6-(2-thiene-3-yl--oxazoles-5-yl)-pyridine-2-yl]-amine;
(4-chloro-pyridine-2-yl)-{ 6-[2-(1H-indoles-5-yl)-oxazoles-5-yl]-pyridine-2-yl }-amine;
(4-chloro-pyridine-2-yl)-[6-(2-thiophene-2-base-oxazoles-5-yl)-pyridine-2-yl]-amine;
(4-chloro-pyridine-2-yl)-[6-(2-furans-2-base-oxazoles-5-yl)-pyridine-2-yl]-amine;
(5-chloro-pyridine-2-yl)-{ 6-[2-(1H-indoles-5-yl)-oxazoles-5-yl]-pyridine-2-yl }-amine;
(5-chloro-pyridine-2-yl)-[6-(2-tetramethyleneimine-1-base-oxazoles-5-yl)-pyridine-2-yl]-amine;
4-{5-[6-(5-chloro-pyridine-2-base is amino)-pyridine-2-yl]-oxazoles-2-yl }-piperazine-2-ketone;
(5-chloro-pyridine-2-yl)-{ 6-[2-(4-methyl-piperazine-1-yl)-oxazoles-5-yl]-pyridine-2-yl }-amine;
(5-chloro-pyridine-2-yl)-6-[2-(2-methoxy ethyl)-methyl-amino-oxazoles-5-yl }-pyridine-2-yl }-amine;
(4,6-dimethyl--pyridine-2-yl)-[6-(2-phenyl-oxazoles-5-yl)-pyridine-2-yl]-amine;
(4,6-dimethyl--pyridine-2-yl)-[6-(2-thiene-3-yl--oxazoles-5-yl)-pyridine-2-yl]-amine;
(4,6-dimethyl--pyridine-2-yl)-{ 6-[2-(1H-indoles-5-yl)-oxazoles-5-yl]-pyridine-2-yl }-amine;
(4,6-dimethyl--pyridine-2-yl)-[6-(2-tetramethyleneimine-1-base-oxazoles-5-yl)-pyridine-2-yl]-amine;
4-{5-[6-(4,6-dimethyl--pyridine-2-base is amino)-pyridine-2-yl]-oxazoles-2-yl }-piperazine-2-ketone;
4-{5-[6-(4-ethyl-pyridine-2-base is amino)-pyridine-2-yl]-oxazoles-2-yl }-piperazine-2-ketone;
2-{6-[2-(3-oxo-piperazine-1-yl)-oxazoles-5-yl]-pyridine-2-base is amino }-different cigarette nitrile;
4-{5-[6-(5-trifluoromethyl-pyridine-2-base is amino)-pyridine-2-yl]-oxazoles-2-yl }-piperazine-2-ketone;
4-{5-[6-(5-trifluoromethyl-pyridine-2-base is amino)-pyridine-2-yl]-oxazoles-2-yl }-piperazine-2-ketone;
(6-{2-[2-(4-methoxyl group-phenyl)-vinyl]-oxazoles-5-yl }-pyridine-2-yl)-[4-(2-morpholine-4-base-oxyethyl group)-pyridine-2-yl]-amine;
(6-{2-[2-(4-methoxyl group-phenyl)-vinyl]-oxazoles-5-yl }-pyridine-2-yl)-(4-methyl-pyrimidine-2-base)-amine;
4-{5-[6-(pyrazine-2-base is amino)-pyridine-2-yl]-oxazoles-2-yl }-piperazine-2-ketone;
{ 6-[2-(4-methyl-piperazine-1-yl)-oxazoles-5-yl]-pyridine-2-yl }-(5-methyl-thiazol-2-yl)-amine;
4-{5-[6-(4-methyl-thiazol-2-yl is amino)-pyridine-2-yl]-oxazoles-2-yl }-piperazine-2-ketone;
{ 6-[2-(4-methyl-piperazine-1-yl)-oxazoles-5-yl]-pyridine-2-yl }-(4-methyl-thiazol-2-yl)-amine;
(4-methyl-pyridine-2-yl)-[3-(2-styryl-oxazoles-5-yl)-phenyl]-amine;
(3-{2-[2-(2,4-two fluoro-phenyl)-vinyl]-oxazole-5-yl }-phenyl)-(4-methyl-pyridine-2-yl)-amine;
(4-methyl-pyridine-2-yl)-[3-(2-thiene-3-yl--oxazoles-5-yl)-phenyl]-amine;
{ 3-[2-(2,4-dimethoxy-phenyl)-oxazoles-5-yl]-phenyl }-(4-methyl-pyridine-2-yl)-amine;
{ 3-[2-(1H-indoles-5-yl)-oxazoles-5-yl]-phenyl }-(4-methyl-pyridine-2-yl)-amine;
1-{5-[3-(4-methyl-pyridine-2-base is amino)-phenyl]-oxazoles-2-yl }-piperidines-4-carboxylic acid amide;
(4-methyl-pyridine-2-yl)-[3-(2-morpholine-4-base-oxazoles-5-yl)-phenyl]-amine;
(4-methyl-pyridine-2-yl)-(3-{2-[(pyridine-2-ylmethyl)-amino]-oxazoles-5-yl }-phenyl)-amine;
[3-(2-benzylamino-oxazoles-5-yl)-phenyl]-(4-methyl-pyridine-2-yl)-amine;
4-{5-[3-(4-methyl-pyrimidine-2--amino)-phenyl]-oxazoles-2-yl }-piperazine-2-ketone;
{ 3-[2-(4-methyl-piperazine-1-yl)-oxazoles-5-yl]-phenyl }-(4-methyl-pyrimidine-2-base)-amine;
(4,6-dimethyl--pyridine-2-yl)-{ 3-[2-(1H-indoles-5-yl)-oxazoles-5-yl]-phenyl }-amine;
3-(4-methyl-pyridine-2-base is amino)-5-[2-(3-oxo-piperazine-1-yl)-oxazoles-5-yl]-cyanobenzene;
3-[2-(4-methyl-piperazine-1-yl)-oxazoles-5-yl]-5-(4-methyl-pyridine-2-base is amino)-cyanobenzene;
4-{5-[3-(4-methyl-pyridine-2-base is amino)-5-trifluoromethoxy-phenyl]-oxazoles-2-yl }-piperazine-2-ketone;
{ 3-[2-(4-methyl-piperazine-1-yl)-oxazoles-5-yl]-5-trifluoromethoxy-phenyl }-(4-methyl-pyridine-2-yl)-amine;
4-{5-[4-methyl-3-(4-methyl-pyridine-2-base is amino)-phenyl]-oxazoles-2-yl }-piperazine-2-ketone;
{ 5-[2-(1H-indoles-5-yl)-oxazoles-5-yl]-2-methyl-phenyl }-(4-methyl-pyridine-2-yl)-amine;
4-[5-(tolyl amino-pyridine-2-yl between 6-)-oxazoles-2-yl]-piperazine-2-ketone;
{ 6-[2-(4-methyl-piperazine-1-yl)-oxazoles-5-yl]-pyridine-2-yl }-tolyl amine;
(6-{2-[(2-methoxyl group-ethyl)-methyl-amino]-oxazoles-5-yl }-pyridine-2-yl)-a tolyl amine;
(4-methyl-pyrimidine-2-base)-[3-(2-pyridine-2-base-thiazole-5-yl)-phenyl]-amine;
(3,5-dimethyl--phenyl)-{ 6-[2-(1H-indoles-5-yl)-oxazoles-5-yl]-pyridine-2-yl }-amine;
4-{5-[6-(4-chloro-phenyl amino)-pyridine-2-yl]-oxazoles-2-yl }-piperazine-2-ketone;
(4-chloro-phenyl)-{ 6-[2-(4-methyl-piperazine-1-yl)-oxazoles-5-yl]-pyridine-2-yl }-amine;
{ 6-[2-(4-methoxyl group-phenyl)-thiazole-5-yl]-pyridine-2-yl }-tolyl-amine;
4-{5-[6-(5-methyl-pyridine-2-base is amino)-pyridine-2-yl]-thiazol-2-yl }-BM.
8. pharmaceutical composition that comprises each described compound among the claim 1-7.
9. one kind comprises make-up composition each described compound, that be used for topical administration among the claim 1-7.
Among the claim 1-7 each described compound in the purposes of making aspect the medicine.
11. according to the purposes described in the claim 10, said medicine is used to treat malignant hematologic disease, myeloproliferative illness, other proliferative disorders, autoimmune disorder, inflammatory diseases, allergic disease and/or sacred disease.
12. according to the purposes described in the claim 11; Wherein, said malignant hematologic disease is acute myelogenous leukemia (AML), myelodysplastic syndrome (MDS), acute one-tenth lymphoblastic leukemia (ALL) and/or chronic lymphocytic leukemia (CML).
13. according to the purposes described in the claim 11, wherein, said proliferative disorders is a cancer.
14. according to the purposes described in the claim 11; Wherein, said autoimmune disorder is multiple sclerosis, psoriasis, inflammatory bowel disease, ulcerative colitis, Crohn disease, rheumatoid arthritis and polyarthritis, part and systemic scleroderma, systemic lupus erythematosus, discoid lupus erythematosus, cutaneous lupus, dermatomyositis, polymyositis, siogren's syndrome, PAN, auto immune enteropathy, atopic dermatitis and/or proliferative glomerulonephritis.
15. according to the purposes described in the claim 11; Wherein, said allergic disease is that asthma, rhinallergosis, allergic sinusitis, supersensitivity syndrome, urticaria, angioedema, atopic dermatitis, contact dermatitis, erythema nodosum, erythema multiforme, cutaneous necrosis property trichodophlebitis and insect bite atopic dermatitis disease and/or blood-sucking parasites infect.
16. according to the purposes described in the claim 11, wherein, said sacred disease is Heng Tingdunshi disease, schizophrenia, parkinson's disease and/or Alzheimer.
17. each described compound plays the purposes aspect the medicine of kinases inhibitor effect among the claim 1-7 in manufacturing.
18. according to the purposes described in the claim 17, wherein, said protein kinase is Flt-3 or syk.
19. one kind is used to treat or prevent experimenter intravital protein kinase, especially Tyrosylprotein kinase, the method for Flt-3 and/or syk relative disease or illness more particularly, said method comprises to said experimenter and gives each described formula I compound among the claim 1-7 of significant quantity.
20. a pharmaceutical composition, said pharmaceutical composition comprise the combination of each described compound and other molecular targeted reagent significant quantity among the claim 1-7.
21. method that is used to prevent or treat malignant hematologic disease, myeloproliferative illness, other proliferative disorders, autoimmune disorder and skin disorder; Said method comprises: so that the amount of result of treatment enough to be provided, to have the human or animal experimenter who needs simultaneously or in a sequence give with the combined claim 1-7 of other molecular targeted reagent in each described compound.
22. in the purposes aspect the manufacturing medicine, said medicine is used to treat malignant hematologic disease, myeloproliferative illness, other proliferative disorders, autoimmune disorder and skin disorder to each described compound together with other molecular targeted reagent among the claim 1-7.
23. compound that is selected from following compound:
(4-methyl-pyridine-2-yl)-(6-oxazole-5-base-pyridine-2-yl)-amine;
[6-(2-chlorine-oxazoles-5-yl)-pyridine-2-yl]-(4-methyl-pyridine-2-yl)-amine;
[6-(2-iodine-oxazoles-5-yl)-pyridine-2-yl]-(4-methyl-pyridine-2-yl)-amine;
2-bromo-6-(2-pyridin-3-yl-thiazole-5-yl)-pyridine;
2-bromo-6-(2-[1,3] dioxolane-2-base-thiazole-5-yl)-pyridine;
[6-(2-[1,3] dioxolane-2-base-thiazole-5-yl)-pyridine-2-yl]-(4-methyl-pyridine-2-yl)-amine;
5-[6-(4-methyl-pyridine-2-base is amino)-pyridine-2-yl]-thiazole-2-formaldehyde.
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| US29422610P | 2010-01-12 | 2010-01-12 | |
| US61/294,226 | 2010-01-12 | ||
| PCT/EP2011/050312 WO2011086085A1 (en) | 2010-01-12 | 2011-01-12 | Thiazole and oxazole kinase inhibitors |
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| US (1) | US8962665B2 (en) |
| EP (1) | EP2523952B1 (en) |
| JP (1) | JP5734313B2 (en) |
| KR (1) | KR101750125B1 (en) |
| CN (1) | CN102812022B (en) |
| AR (1) | AR079993A1 (en) |
| AU (1) | AU2011206621B2 (en) |
| CA (1) | CA2786800C (en) |
| CL (1) | CL2012001938A1 (en) |
| EA (1) | EA022188B1 (en) |
| ES (1) | ES2539170T3 (en) |
| HK (1) | HK1177205A1 (en) |
| IL (1) | IL220863A (en) |
| MX (1) | MX2012008083A (en) |
| NZ (1) | NZ601143A (en) |
| SG (1) | SG182480A1 (en) |
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| CN103396400A (en) * | 2013-07-16 | 2013-11-20 | 浙江医药高等专科学校 | Pyrazole amide compounds, and preparation method and application thereof |
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| CN103382198B (en) * | 2013-07-16 | 2014-11-19 | 浙江医药高等专科学校 | Pyrazole amide compound, and preparation method thereof and application |
| CN103396400B (en) * | 2013-07-16 | 2014-12-17 | 浙江医药高等专科学校 | Pyrazole amide compounds, and preparation method and application thereof |
| CN104458671A (en) * | 2013-09-12 | 2015-03-25 | 中国药科大学 | High flux screening method for screening tropomyosin-related kinase B inhibitor |
| CN104458676A (en) * | 2013-09-12 | 2015-03-25 | 中国药科大学 | High flux screening method for screening lymphocytes specific kinase inhibitor |
| CN106414433A (en) * | 2014-03-24 | 2017-02-15 | Ab科学有限公司 | Diazaspiroalkaneone-substituted oxazole derivatives as spleen tyrosine kinase inhibitors |
| CN109666028A (en) * | 2017-10-16 | 2019-04-23 | 苏州大学 | 1,3,4- thiadiazole heterocycles with activity of hedgehog path antagonist |
Also Published As
| Publication number | Publication date |
|---|---|
| AU2011206621A1 (en) | 2012-08-02 |
| AU2011206621B2 (en) | 2016-04-14 |
| US8962665B2 (en) | 2015-02-24 |
| EA022188B1 (en) | 2015-11-30 |
| HK1177205A1 (en) | 2013-08-16 |
| NZ601143A (en) | 2014-10-31 |
| US20130035331A1 (en) | 2013-02-07 |
| ES2539170T3 (en) | 2015-06-26 |
| TW201132635A (en) | 2011-10-01 |
| KR20120115515A (en) | 2012-10-18 |
| IL220863A (en) | 2017-11-30 |
| MX2012008083A (en) | 2012-08-15 |
| SG182480A1 (en) | 2012-08-30 |
| EP2523952B1 (en) | 2015-03-04 |
| EP2523952A1 (en) | 2012-11-21 |
| KR101750125B1 (en) | 2017-06-22 |
| WO2011086085A1 (en) | 2011-07-21 |
| EA201290600A1 (en) | 2013-01-30 |
| CA2786800C (en) | 2018-02-27 |
| CL2012001938A1 (en) | 2014-03-07 |
| JP5734313B2 (en) | 2015-06-17 |
| CA2786800A1 (en) | 2011-07-21 |
| CN102812022B (en) | 2016-02-03 |
| AR079993A1 (en) | 2012-03-07 |
| JP2013517244A (en) | 2013-05-16 |
| TWI523852B (en) | 2016-03-01 |
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